Novel 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 and 65577 molecules and uses therefor

ABSTRACT

The invention provides isolated nucleic acids molecules, designated 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 and 65577 nucleic acid molecules. The invention also provides antisense nucleic acid molecules, recombinant expression vectors containing 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 and 65577 nucleic acid molecules, host cells into which the expression vectors have been introduced, and nonhuman transgenic animals in which a 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 gene has been introduced or disrupted. The invention still further provides isolated 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 proteins, fusion proteins, antigenic peptides and anti-27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 antibodies. Diagnostic and therapeutic methods utilizing compositions of the invention are also provided.

RELATED APPLICATIONS

[0001] The present application is a continuation-in-part of U.S. patentapplication Ser. No. 09/950,370, filed Sep. 10, 2001 (pending), whichclaims the benefit of U.S. Provisional Application Serial No.60/231,084, filed Sep. 8, 2000. The present application is also acontinuation-in-part of U.S. patent application Ser. No. 10/294,039,filed Nov. 13, 2002 (pending), which claims the benefit of U.S.Provisional Application Serial No. 60/338,587, filed Nov. 13, 2001. Thepresent application is also a continuation-in-part of U.S. patentapplication Ser. No. 10/266,035, filed Oct. 7, 2002 (pending), whichclaims the benefit of U.S. Provisional Application Serial No.60/328,198, filed Oct. 9, 2001. The present application is also acontinuation-in-part of U.S. patent application Ser. No. 09/717,926,filed Nov. 21, 2000 (pending), which claims the benefit of U.S.Provisional Application Serial No. 60/214,707, filed Jun. 27, 2000. Thepresent application is also a continuation-in-part of U.S. patentapplication Ser. No. 10/268,036, filed Oct. 9, 2002 (pending), whichclaims the benefit of U.S. Provisional Application Serial No.60/327,820, filed Oct. 9, 2001. The present application is also acontinuation-in-part of U.S. patent application Ser. No. 09/922,138,filed Aug. 03, 2001 (pending), which claims the benefit of U.S.Provisional Application Serial No. 60/229,299, filed Sep. 1, 2000. Thepresent application is also a continuation-in-part of U.S. patentapplication Ser. No. 09/945,327, filed Aug. 31, 2001 (pending), whichclaims the benefit of U.S. Provisional Application Serial No.60/229,425, filed Aug. 31, 2000. The present application is also acontinuation-in-part of U.S. patent application Ser. No. 10/163,316,filed Jun. 5, 2002 (pending), which claims the benefit of U.S.Provisional Application Serial No. 60/297,863, filed Jun. 13, 2001. Thepresent application is also a continuation-in-part of U.S. patentapplication Ser. No. 10/103,377, filed Mar. 21, 2002 (pending), whichclaims the benefit of U.S. Provisional Application Serial No.60/278,347, filed Mar. 23, 2001. The entire contents of each of theabove-referenced patent applications are incorporated herein by thisreference.

BACKGROUND OF THE INVENTION

[0002] The enormous variety of biochemical reactions that comprise lifeare nearly all mediated by a series of biological catalysts known asenzymes. Enzymes are proteins which possess specific catalyticactivities that enable them to catalyze a series of reactions, henceenabling metabolic pathways to degrade and to reconstruct productsneeded to maintain organisms. By the binding of substrates throughgeometrically and physically complementary reactions, enzymes arestereospecific in binding substrates as well as in catalyzing reactions.The stringency for this stereospecificity varies as some enzymes aremore specific to the identity of their substrates, while others arecapable of binding multiple substrates and can catalyze numerous typesof reactions.

[0003] Examples of enzymes include, for example, phospholipases, serinecarboxypeptidases, trypsin-like serine proteases, aldehydedehydrogenases, ubiquitin-protein ligases, protein kinases, hydrolasesand matrix metalloproteinases. Such enzymes have the ability to, forexample: to reversibly phosphorylate proteins in order to regulateprotein activity in eukaryotic cells; to catalyze the hydrolysis of anacyl or phosphoacyl bond of a phospholipids; to modulate removal ofCOOH-terminal residues, i.e., having carboxypeptidase activity; tomodulate the transfer of an acyl group from a donor to an acceptormolecule, i.e., having acyltransferase activity; to degrade proteins; tophosphorylate carbohydrates; to oxidate an aldehyde; to modulateubiquitination of a substrate, e.g., a protein targeted for degradation;to modulate substrate specificity for ubiquitination; to reversiblyphosphorylate proteins in order to regulate protein activity ineukaryotic cells; to interact with cytotoxins and metabolites (e.g.,lactoylglutathione, a glutathione-conjugated metabolite, ahydroxycarboxylic acid, and the like); to catalyze the metobolism of acytotoxin or metabolite; to hydrolyze a thioester containing compound(e.g., lactoylglutathione, and the like); to catalyze the formation of athioester conjugation on a substrate (e.g., lactate or ahydroxycarboxylic acid); to cleave or modulate the degredation ofproteins or peptides of the extracellular matrix; to catalyze ormodulate catalysis of cleavage of covalent bonds within or between aminoacid residues (e.g., in extracellular matrix, cell-surface, andextracellular proteins); as well as many others. Accordingly, thereexists a need to identify additional human enzymes, for example, for useas disease markers and as targets for identifying various therapeuticmodulators.

SUMMARY OF THE INVENTION

[0004] The present invention is based, at least in part, on thediscovery of novel nucleic acid molecules and proteins encoded by suchnucleic acid molecules, referred to herein as “27877, 18080, 14081,32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577”. The 27877,18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577nucleic acid and protein molecules of the present invention are usefulas modulating agents in regulating a variety of cellular processes,e.g., including, but not limited to cell proliferation, differentiation,growth and division. In particular, these nucleic acid molecules will beadvantageous in the regulation of any cellular function, uncontrolledproliferation and differentiation, such as in cases of cancer.Accordingly, in one aspect, this invention provides isolated nucleicacid molecules encoding 27877, 18080, 14081, 32140, 50352, 16658, 14223,16002, 50566, 65552 or 65577 proteins or biologically active portionsthereof, as well as nucleic acid fragments-suitable as primers orhybridization probes for the detection of 27877, 18080, 14081, 32140,50352, 16658, 14223, 16002, 50566, 65552 or 65577-encoding nucleicacids.

[0005] The nucleotide sequence of the cDNA encoding 27877, 18080, 14081,32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577, and the aminoacid sequence of 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577 polypeptides are depicted in Table 1. TABLE 1Sequences of the invention ATCC Gene accession Name cDNA Protein CodingRegion number 27877 SEQ ID SEQ ID SEQ ID PTA-3217 NO:1 and 4 NO:2 and 5NO:3 and 6 18080 SEQ ID NO:11 SEQ ID NO:12 SEQ ID NO:13 N/A 14081 SEQ IDNO:20 SEQ ID NO:21 SEQ ID NO:22 N/A 32140 SEQ ID NO:25 SEQ ID NO:26 SEQID NO:27 PTA-3424 50352 SEQ ID NO:29 SEQ ID NO:30 SEQ ID NO:31 N/A 16658SEQ ID NO:35 SEQ ID NO:36 SEQ ID NO:37 N/A 14223 SEQ ID NO:38 SEQ IDNO:39 SEQ ID NO:40 N/A 16002 SEQ ID NO:41 SEQ ID NO:42 SEQ ID NO:43 N/A50566 SEQ ID NO:73 SEQ ID NO:74 SEQ ID NO:75 N/A 65552 SEQ ID NO:76 SEQID NO:77 SEQ ID NO:78 N/A 65577 SEQ ID NO:86 SEQ ID NO:87 SEQ ID NO:88N/A

[0006] Accordingly, in one aspect, the invention features a nucleic acidmolecule which encodes a 27877, 18080, 14081, 32140, 50352, 16658,14223, 16002, 50566, 65552 or 65577 protein or polypeptide, e.g., abiologically active portion of the 27877, 18080, 14081, 32140, 50352,16658, 14223, 16002, 50566, 6555,2 or 65577 protein. In a preferredembodiment, the isolated nucleic acid molecule encodes a polypeptidehaving the amino acid sequence of SEQ ID NO: 2, 5, 12, 21, 26, 30, 36,39, 42, 74, 77 or 87. In other embodiments, the invention providesisolated 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566,65552 or 65577 nucleic acid molecules having the nucleotide sequenceshown in SEQ ID NO: 1, 3, 4, 6, 11, 13, 20, 22, 25, 27, 29, 31, 35, 37,38, 40, 41, 43, 73, 75, 76, 78, 86 or 88 or the nucleotide sequence ofthe DNA insert of the plasmid deposited with ATCC Accession NumberPTA-3217 or PTA-3424. In still other embodiments, the invention providesnucleic acid molecules that are substantially identical (e.g., naturallyoccurring allelic variants) to the nucleotide sequence shown in SEQ IDNO: 1, 3, 4, 6, 11, 13, 20, 22, 25, 27, 29, 31, 35, 37, 38, 40, 41, 43,73, 75, 76, 78, 86 or 88 or the nucleotide sequence of the DNA insert ofthe plasmid deposited with ATCC Accession Number PTA-3217 or PTA-3424.In other embodiments, the invention provides a nucleic acid moleculewhich hybridizes under a stringent hybridization condition as describedherein to a nucleic acid molecule comprising the nucleotide sequence ofSEQ ID NO: 1, 3, 4, 6, 11, 13, 20, 22, 25, 27, 29, 31, 35, 37, 38, 40,41, 43, 73, 75, 76, 78, 86 or 88 or the nucleotide sequence of the DNAinsert of the plasmid deposited with ATCC Accession Number PTA-3217 orPTA-3424, wherein the nucleic acid encodes a full length 27877, 18080,14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 proteinor an active fragment thereof.

[0007] In a related aspect, the invention further provides nucleic acidconstructs which include a 27877, 18080, 14081, 32140, 50352, 16658,14223, 16002, 50566, 65552 or 65577 nucleic acid molecule describedherein. In certain embodiments, the nucleic acid molecules of theinvention are operatively linked to native or heterologous regulatorysequences. Also included are vectors and host cells containing the27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or65577 nucleic acid molecules of the invention e.g., vectors and hostcells suitable for producing polypeptides.

[0008] In another related aspect, the invention provides nucleic acidfragments suitable as primers or hybridization probes for the detectionof 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552or 65577-encoding nucleic acids.

[0009] In still another related aspect, isolated nucleic acid moleculesthat are antisense to a 27877, 18080, 14081, 32140, 50352, 16658, 14223,16002, 50566, 65552 or 65577 encoding nucleic acid molecule areprovided.

[0010] In another aspect, the invention features 27877, 18080, 14081,32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 polypeptides,and biologically active or antigenic fragments thereof that are useful,e.g., as reagents or targets in assays applicable to treatment anddiagnosis of 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577-associated disorders. In another embodiment, theinvention provides 27877, 18080, 14081, 32140, 50352, 16658, 14223,16002, 50566, 65552 or 65577 polypeptides having a 27877, 18080, 14081,32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 activity.

[0011] In other embodiments, the invention provides 27877, 18080, 14081,32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 polypeptides,e.g., a 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566,65552 or 65577 polypeptide having the amino acid sequence shown in SEQID NO: 2, 5, 12, 21, 26, 30, 36, 39, 42, 74, 77 or 87 or the amino acidsequence encoded by the cDNA insert of the plasmid deposited with ATCCAccession Number PTA-3217 or PTA-3424; an amino acid sequence that issubstantially identical to the amino acid sequence shown in SEQ ID NO:2, 5, 12, 21, 26, 30, 36, 39, 42, 74, 77 or 87 or the amino acidsequence encoded by the cDNA insert of the plasmid deposited with ATCCAccession Number PTA-3217 or PTA-3424; or an amino acid sequence encodedby a nucleic acid molecule having a nucleotide sequence which hybridizesunder a stringent hybridization condition as described herein to anucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:1, 3, 4, 6, 11, 13, 20, 22, 25, 27, 29, 31, 35, 37, 38, 40, 41, 43, 73,75, 76, 78, 86 or 88 or the nucleotide sequence of the insert of theplasmid deposited with ATCC Accession Number PTA-3217 or PTA-3424,wherein the nucleic acid encodes a full length 27877, 18080, 14081,32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 protein or anactive fragment thereof.

[0012] In a related aspect, the invention further provides nucleic acidconstructs which include a 27877, 18080, 14081, 32140, 50352, 16658,14223, 16002, 50566, 65552 or 65577 nucleic acid molecule describedherein.

[0013] In a related aspect, the invention provides 27877, 18080, 14081,32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 polypeptides orfragments operatively linked to non-27877, 18080, 14081, 32140, 50352,16658, 14223, 16002, 50566, 65552 or 65577 polypeptides to form fusionproteins.

[0014] In another aspect, the invention features antibodies andantigen-binding fragments thereof, that react with, or more preferablyspecifically or selectively bind 27877, 18080, 14081, 32140, 50352,16658, 14223, 16002, 50566, 65552 or 65577 polypeptides.

[0015] In another aspect, the invention provides methods of screeningfor compounds that modulate the expression or activity of the 27877,18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577polypeptides or nucleic acids.

[0016] In still another aspect, the invention provides a process formodulating 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577 polypeptide or nucleic acid expression oractivity, e.g., using the compounds identified in the screens describedherein. In certain embodiments, the methods involve treatment ofconditions related to aberrant activity or expression of the 27877,18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577polypeptides or nucleic acids, such as conditions or disorders involvingaberrant or deficient 27877, 18080, 14081, 32140, 50352, 16658, 14223,16002, 50566, 65552 or 65577 expression. Examples of such disordersinclude, but are not limited to cellular proliferative and/ordifferentiative disorders, brain disorders, blood vessel disorders,platelet disorders, breast disorders, colon disorders, kidney disorders,lung disorders, ovarian disorders, prostate disorders, hematopoeiticdisorders, pancreatic disorders, skeletal muscle disorders, testiculardisorders, skin disorders, hormonal disorders, disorders associated withbone metabolism, immune e.g., inflammatory, disorders, cardiovasculardisorders, endothelial cell disorders, liver disorders, viral diseases,pain, metabolic disorders, anemias, angiogenesis, neoplastic disorders,endocrine disorders, neurological disorders and heart disorders.

[0017] The invention also provides assays for determining the activityof or the presence or absence of 27877, 18080, 14081, 32140, 50352,16658, 14223, 16002, 50566, 65552 or 65577 polypeptides or nucleic acidmolecules in a biological sample, including for disease diagnosis.

[0018] In a further aspect, the invention provides assays fordetermining the presence or absence of a genetic alteration in a 27877,18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577polypeptide or nucleic acid molecule, including for disease diagnosis.

[0019] In another aspect, the invention features a two dimensional arrayhaving a plurality of addresses, each address of the plurality beingpositionally distinguishable from each other address of the plurality,and each address of the plurality having a unique capture probe, e.g., anucleic acid or peptide sequence. At least one address of the pluralityhas a capture probe that recognizes a 27877, 18080, 14081, 32140, 50352,16658, 14223, 16002, 50566, 65552 or 65577 molecule. In one embodiment,the capture probe is a nucleic acid, e.g., a probe complementary to a27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or65577 nucleic acid sequence. In another embodiment, the capture probe isa polypeptide, e.g., an antibody specific for 27877, 18080, 14081,32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 polypeptides.Also featured is a method of analyzing a sample by contacting the sampleto the aforementioned array and detecting binding of the sample to thearray.

[0020] Other features and advantages of the invention will be apparentfrom the following detailed description, and from the claims.

DETAILED DESCRIPTION OF THE INVENTION

[0021] Human 27877

[0022] The invention relates to a novel phospholipase protein that canexist in at least two forms, herein designated the ‘short’ and ‘long’forms. The phospholipase (i.e., in either form) is referred to herein as“27877,” and can exhibit phospholipase A1 activity. Phosphatidic acidsare preferred substrates for the catalytic activity of 27877, althoughnon-phosphatidic acid phospholipids can also act as substrates for theenzyme.

[0023] The human short form of 27877 sequence (SEQ ID NO: 1), which isapproximately 2981 nucleotides long including untranslated regions,contains a predicted methionine-initiated coding sequence of about 2622nucleotides (nucleotides 202-2823 of SEQ ID NO: 1; nucleotides 1-2622 ofSEQ ID NO: 3), not including the terminal codon. The coding sequenceencodes a 874 amino acid protein (SEQ ID NO: 2).

[0024] The long form human 27877 cDNA sequence (SEQ ID NO: 4), which isapproximately 3065 nucleotide residues long including non-translatedregions, contains a predicted methionine-initiated coding sequence ofabout 2706 nucleotide residues, excluding termination codon (i.e.,nucleotide residues 202-2907 of SEQ ID NO: 4; nucleotides 1-2706 SEQ IDNO: 6). The coding sequence encodes a 902 amino acid protein(SEQ ID NO:5).

[0025] Human 27877 proteins contain a predicted transmembrane domain atabout amino acid residues 620-636 of SEQ ID NOs: 2 and 5. 27877 proteinscan thus exist in a membrane bound form comprising two extra-membranedomains (the first corresponding to about amino acid residues 1-619 ofeach of SEQ ID NOs: 2 and 5, and the second corresponding to about aminoacid residues 637 through the carboxyl terminus of each of thesesequences) separated by a transmembrane domain. In one embodiment, a27877 protein can exist in a form in which the region corresponding toabout amino acid residues 1-619 of each of SEQ ID NOs: 2 and 5 isoriented on the non-lumenal side of a membrane (e.g., a cell membrane ora nuclear or other organellar membrane) and the region corresponding toabout amino acid residues 637 through the carboxyl terminus of each ofSEQ ID NOs: 2 and 5 is oriented on the lumenal side of the membrane. Inanother embodiment, the regions have the opposite orientations. In stillanother embodiment, the 27877 protein exists in a soluble form (i.e.,not inserted in a membrane).

[0026] The human 27877 protein has predicted N-glycosylation sites (Pfamaccession number PS00001) at about amino acid residues 486-489 and690-693 of each of SEQ ID NOs: 2 and 5; a predicted cAMP-/cGMP-dependentprotein kinase phosphorylation site (Pfam accession number PS00004) atabout amino acid residues 145-148 of each of SEQ ID NOs: 2 and 5;predicted protein kinase C phosphorylation sites (Pfam accession numberPS00005) at about amino acid residues 8-10, 99-101, 180-182, 189-191,343-345, 367-369, 375-377, 588-590, 733-735, and 778-780 of each of SEQID NOs: 2 and 5; predicted casein kinase II phosphorylation sites (Pfamaccession number PS00006) located at about amino acid residues 92-95,104-107, 141-144, 226-229, 244-247, 271-274, 271-274, 355-358, 399-402,450-453, 488-491, 575-578, 713-716, 778-781, 782-785, 813-816, and846-849 of SEQ ID NO: 2 (about amino acid residues 92-95, 104-107,141-144, 226-229, 244-247, 271-274, 271-274, 355-358, 399-402, 450-453,488-491, 575-578, 713-716, 778-781, 782-785, and 874-877 of SEQ ID NO:5); a predicted tyrosine kinase phosphorylation site (Pfam accessionnumber PS00007) at about amino acid residues 579-586 of each of SEQ IDNOs: 2 and 5; and predicted N-myristoylation sites (Pfam accessionnumber PS00008) at about amino acid residues 18-23, 35-40, 109-114,133-138, 139-144, 151-156, 530-535, 541-546, 601-606, 624-629, 635-640,761-766, and 828-833 of SEQ ID NO: 2 (about amino acid residues 18-23,35-40, 109-114, 133-138, 139-144, 151-156, 530-535, 541-546, 601-606,624-629, 635-640, 761-766, and 856-861 of SEQ ID NO: 5).

[0027] For general information regarding PFAM identifiers, PS prefix andPF prefix domain identification numbers, refer to Sonnhammer et al.(1997, Protein 28:405-420).

[0028] A plasmid containing the nucleotide sequence encoding the shortform of human 27877 was deposited with American Type Culture Collection(ATCC®), 10801 University Boulevard, Manassas, Va. 20110-2209, on Mar.23, 2001 and assigned accession number PTA-3217. A plasmid containingthe nucleotide sequence encoding the short form of human 27877 wasdeposited with ATCC® on Mar. 23, 2001 and assigned accession numberPTA-3217. These deposits will be maintained under the terms of theBudapest Treaty on the International Recognition of the Deposit ofMicroorganisms for the Purposes of Patent Procedure. These deposits weremade merely as a convenience for those of skill in the art and are notan admission that a deposit is required pursuant to 35 U.S.C. § 112.

[0029] Phospholipids (sometimes designated ‘phosphatides’) are mixedesters of fatty acids and phosphoric acid with an alcohol such asglycerol or sphingosine. Glycerol-based phospholipids have a phosphorylmoiety esterified with a hydroxyl moiety at one end of the glycerolmoiety and at least one fatty acyl moiety esterified with the remainingglyceroyl hydroxyl moieties. The phosphoryl moiety can be esterifiedwith an additional moiety (e.g., choline, ethanolamine, serine, inositolor an inositol phosphate), some of which (e.g., choline orinositol-4-phosphate) can have a charged moiety. Phospholipids are theprimary lipid component of most animal cellular membranes. Most membranephospholipids comprise two fatty acyl moieties, often including both asaturated fatty acyl moiety and an unsaturated fatty acyl moiety.

[0030] Phospholipases are a ubiquitous class of enzymes that catalyzehydrolysis of phospholipids. Multiple classes of phospholipases areknown, and phospholipases can be classified based on the phospholipidbond of which the enzyme catalyzes hydrolysis. For example,phospholipase A1 enzymes cleave the acyl moiety esterified at theglyceroyl hydroxyl moiety most distal from the phosphoryl moiety in aphospholipid. One known phospholipase A1 enzyme is designatedphosphatidic acid-preferring phospholipase A1 and was isolated frombovine testis (Higgs et al., 1998, J. Biol. Chem. 273:5468-5477).Phospholipase A2 enzymes more specifically cleave the acyl moiety at theglyceroyl hydroxyl moiety adjacent the phosphoryl moiety of aphospholipid. Phospholipase B enzymes can cleave acyl moieties fromeither of these positions. Phospholipase C enzymes cleave the phosphorylmoiety from the glycerol backbone of a glycerophosphatide, andphospholipase D enzymes can cleave phosphatidic acid from a moiety boundwith the phosphoryl moiety.

[0031] Because hydrolyzed phospholipids and products generated therefrom(e.g., arachidonic acid and lipoxygenase- and cyclooxygenase-catalyzedreaction products such as prostaglandins) can act as second messengersin cellular signaling systems, expression of many phospholipases ishighly regulated in cells. Many and complex array of regulatorymechanisms have been described for regulating phospholipase expression,some involving cytoplasmic proteins, notably G-proteins, as well asdifferent effector lipids (e.g., phosphatidylinositol-4,5-biphosphate)or Ca²⁺. Phospholipase expression can be modulated by numerous signaltransduction pathways, and phospholipases can also participate innumerous signal transduction pathways.

[0032] Numerous phospholipases have been described. However, in view ofthe widespread and critical nature of phospholipase activities in normaland pathological physiological processes, a need exists foridentification of further members of this protein family. The presentinvention satisfies this need by providing a novel human phospholipase.

[0033] The 27877 protein contains a significant number of structuralcharacteristics in common with members of the phospholipase family. Onecharacteristic of the lipase family of enzymes is the presence of fiveamino acids that have the consensus sequence Xaa₁-Xaa₂-Ser-Xaa₃-Gly (SEQID NO: 10), wherein Xaa₁ is Gly or Ser and each of Xaa₂ and Xaa₃ can beany amino acid residue. This sequence is highly conserved among lipasesand contains the active serine nucleophile present in,most lipases. Thissequence is present in the 27877 amino acid sequence asSer-His-Ser-Leu-Gly (SEQ ID NO: 9), with the first amino acid of thisconsensus sequence present in the 27877 sequence being a serine ratherthan a glycine. The predicted active serine nucleophile is located atamino acid position 539 of both the short form and the long form of thehuman 27877 protein. Higgs et al. describe a bovine phosphatidicacid-preferring phospholipase A1 (PA-PLA1) which comprises an identicalversion of the consensus sequence (i.e., Ser-His-Ser-Leu-Gly, SEQ ID NO:9) wherein the active serine nucleophile is located at amino acidposition 540 (1998, J. Biol. Chem. 273:5468-5477). These characteristicsindicate that human 27877 protein is an active phospholipase molecule.

[0034] In another embodiment, a 27877 protein includes at least onetransmembrane domain. As used herein, the term “transmembrane domain”includes an amino acid sequence of about 5 amino acid residues in lengththat spans the plasma membrane. More preferably, a transmembrane domainincludes about at least 10, 15, or 17 amino acid residues and spans amembrane. Transmembrane domains are rich in hydrophobic residues, andtypically have an alpha-helical structure. In a preferred embodiment, atleast 50%, 60%, 70%, 80%, 90%, or 95% or more of the amino acids of atransmembrane domain are hydrophobic, e.g., leucines, isoleucines,tyrosines, or tryptophans. Transmembrane domains are described in, forexample, Zagotta W. N. et al. (1996, Annu. Rev. Neurosci. 19: 235-263),the contents of which are incorporated herein by reference. Amino acidresidues 1 to about 620-636 of SEQ ID NOs: 2 and 5 comprise atransmembrane domain in a 27877 protein.

[0035] The 27877 molecules of the present invention can further includeone or more of the N-glycosylation, cAMP-/cGMP-dependent protein kinasephosphorylation, protein kinase C phosphorylation, casein kinase IIphosphorylation, tyrosine kinase, and N-myristoylation sites describedherein, and preferably comprises most or all of them.

[0036] In an alignment of the nucleotide sequences of cDNAs encoding thelong form of the human 27877 protein and the bovine PA-PLA1 (SEQ ID NO:7)(made using the ALIGN software, using default parameters, includinggap opening penalty=12, and gap extension penalty=2), the nucleic acidsequences of the cDNAs are 87.6% identical. An alignment (made using theALIGN software, using default parameters, including gap openingpenalty=12, and gap extension penalty=2) of the amino acid sequences ofthe long form of the 27877 protein and the bovine PA-(SEQ ID NO: 8), theamino acid sequences of the proteins are 88.5% identical. The similarityof the sequences of human 27877 protein and bovine PA-PLA1 indicatesthat the two proteins exhibit common activities.

[0037] A hydropathy plot of the short and long forms of human 27877 wasperformed. Polypeptides of the invention include fragments whichinclude: all or part of a hydrophobic sequencee.g., the sequence ofabout residues 620-636 of either of SEQ ID NOs: 2 and 5; all or part ofa hydrophilic sequence,e.g., the sequence of residues 200-215 of eitherof SEQ ID NOs: 2 and 5; a sequence which includes a cysteine residue; ora glycosylation site.

[0038] Because the 27877 polypeptides of the invention can modulate27877-mediated activities, they can be used to develop novel diagnosticand therapeutic agents for 27877-mediated or related disorders, asdescribed below.

[0039] As used herein, a “27877 activity,” “biological activity of27877,” or “functional activity of 27877,” refers to an activity exertedby a 27877 protein, polypeptide or nucleic acid molecule on, forexample, a 27877-responsive cell or on a 27877 substrate (e.g., aprotein substrate) as determined in vivo or in vitro. In one embodiment,a 27877 activity is a direct activity, such as association with a 27877target molecule. A “target molecule” or “binding partner” of a 27877protein is a molecule with which the 27877 protein binds or interacts innature. In an exemplary embodiment, such a target molecule is a 27877receptor. A 27877 activity can also be an indirect activity, such as acellular signaling activity mediated by interaction of the 27877 proteinwith a 27877 receptor.

[0040] The 27877 molecules of the present invention are predicted tohave similar biological activities as phospholipase family members. Forexample, the 27877 proteins of the present invention can have one ormore of the following activities: catalyzing hydrolysis of an acyl orphosphoacyl bond of a phospholipid; catalyzing production of arachidonicacid; modulating generation of a prostaglandin; modulating generation ofa lipoxygenase reaction product formed from arachidonic acid; modulatingtumor cell invasion or metastasis; modulating tumorigenesis; modulatinga response to infection; modulating inflammation; modulating a cellularresponse to inflammation; modulating pain impulse generation; modulatingpain impulse transmission; modulating pain sensation modulatingapoptosis; modulating growth of erythroid lineage precursor cells;modulating differentiation of erythroid lineage precursor cells; andmodulating production of erythrocytes. Thus, 27877 molecules describedherein can act as novel diagnostic targets and therapeutic agents forprognosticating, diagnosing, preventing, inhibiting, alleviating, orcuring phospholipase-, lipoxygenase-, and cyclooxygenase-relateddisorders.

[0041] Other activities, as described below, include the ability tomodulate function, survival, morphology, proliferation and/ordifferentiation of cells of tissues in which 27877 molecules areexpressed. Thus, the 27877 molecules can act as novel diagnostic targetsand therapeutic agents for controlling disorders involving aberrantactivities of these cells. 27877 molecules can also act as noveldiagnostic targets and therapeutic agents for controlling cellularproliferative and/or differentiative disorders (e.g., hematopoieticneoplastic disorders, carcinoma, sarcoma, metastatic disorders orhematopoietic neoplastic disorders, e.g., leukemias. A metastatic tumorcan arise from a multitude of primary tumor types, including but notlimited to those of prostate, colon, lung, breast, and liver origin.

[0042] Based on data generated by reverse-transcriptase PCR sequencedetection (i.e., “TAQMAN®D”) techniques using a panel of tissuesobtained from selected human tissues, a high level of 27877 expressionwas observed in normal brain cortex. Brain cortex is the tissue locationof numerous physiological activities, in each of which 27877 proteinscan have a role. By way of example, interconnections that are formed innormal brain cortex tissue can mediate muscular and intellectuallearning, and can facilitate ‘neuronal learning’ processes wherebyphysical stimuli can more easily evoke a sensation of pain over time.Because 27877 protein is involved in cell signaling and differentiationprocesses, 27877 molecules can be used to modulate muscular,intellectual, and neuronal learning processes in humans.

[0043] Various neurodegenerative disorders are known to involve aberrantfunctioning of cell signaling mechanisms. For example, Alzheimer'sdisease is often characterized by generation and accumulation ofneurofibrillary tangles containing large quantities of abnormallyphosphorylated tau protein. Although the intracellular signalingmechanisms that affect tau phosphorylation have not been fullyelucidated, it is known that numerous signaling proteins (includingthose which affect intracellular phosphate pools, such as kinase,phosphatases, and phospholipases) can affect the phosphorylation stateof tau protein. 27877 protein can influence the phosphorylation state oftau protein, and molecules that affect expression, activity, or cellularlevel of 27877 protein can be used to modulate phosphate-mediatedcellular signaling. Thus, these molecules can be used to treat patientsafflicted with neurodegenerative disorders such as Alzheimer's disease.

[0044] Because 27877 protein is involved in cell differentiationprocesses and is expressed in normal brain cortex, modulatingexpression, activity, or cellular level of 27877 protein can improverecovery of brain tissue following ischemic traumas, such as thoseassociated with stroke and traumatic brain injuries.

[0045] Expression of 27877 was also detected in normal brainhypothalamus tissue, astrocytes, and ovary tissue. Each of these cell ortissue types is characterized by growth or proliferation during at leastcertain portions of the adult lifespan. Involvement of 27877 protein incell differentiation processes indicates that 27877 molecules caninfluence growth and proliferation of cells in these tissues, such asdifferentiation of precursor cells (e.g., neuronal stem cells orpartially differentiated brain or ovarian cell types) in a process thatleads to formation of the fully-differentiated tissue.

[0046] TAQMAN® analysis performed on a panel of selected humanhematological tissues indicated high levels of 27877 expression in fetalliver, bone marrow erythrocytes, in vitro generated erythroid lineageprogenitor cells at day 6 through day 12, in vitro generated burstforming unit-erythroid (BFU-E), and BFU-E exposed to erythropoietin for3 days. Each of these tissues and cell types is involved indifferentiation of blood cells and blood cell precursors. 27877 was mosthighly expressed in cells of the myeloid line, particularly indifferentiating erythroid lineage progenitor cells (includingburst-forming units of erythroid lineage; “BFU-E”) and bone marrowerythrocytes (i.e., GPA+ cells of bone marrow). BFU-E that were exposedto erythropoietin for 3 days expressed 27877 at an even greater level.Expression of 27877 was also observed in bone marrow tissue (includingerythroid progenitor cells which expressed GPA at a low level),mobilized peripheral blood, and cord blood CD34+ cells.

[0047] These expression data indicate that 27877 has a role indifferentiation of erythroid cells, such as in terminal differentiationof these cells to form erythrocytes. An increase in intracellular 27877activity can lead to increased intracellular production of phosphatidicacid (PA). PA accumulation leads to cessation of cell growth, and thismay be a mechanism by which the activity of 27877 protein can modulatethe rate or extent of erythroid cell differentiation. PA is also knownto act as an intracellular second messenger, and can regulate growth anddifferentiation of cells in which it is expressed. Involvement of 27877protein in regulation of intracellular PA indicates that 27877 moleculescan be used to modulate erythroid cell growth and differentiation, bothin normal tissues and tissues affected by a disorder, particularlydisorders which affect erythroid cell growth or differentiation.

[0048] 27877 molecules can be used to enhance growth and differentiationof erythroid precursor cells to induce formation of erythrocytes andalleviate the severity of the anemia. Naturally, 27877 molecules canalso be used to inhibit or prevent anemia in situations in which anemiais anticipated (e.g., in advance of administering a hemolyticmedication).

[0049] 27877 molecules can be used in non-diseased humans in order toincrease erythrocyte production. Enhanced erythrocyte production can bebeneficial, for example, during or prior to periods of intense physicalexertion or exposure to a relatively oxygen-poor altitude (e.g., at highaltitudes). These molecules can also be used to enhance oxygenabsorption by humans whose oxygen intake may be hampered byenvironmental contaminants (e.g., carbon monoxide or tobacco smoke) orby physical infirmity (e.g., diaphragm weakness associated withtraumatic injury or pneumonia).

[0050] Other disorders associated with aberrant growth and proliferationof erythrocytes include polycythemias, which are associated with anoverabundance of erythrocytes or hemoglobin. Examples of polycythemiasthat can be treated using 27877 molecules include polycythemia vera,secondary polycythemia, and relative polycythemia.

[0051] Gene Expression of 27877

[0052] Expression of 27877 was assessed in a variety of cell and tissuetypes using a standard TAQMAN™ PCR-based sequence detection procedure.The data collected from these experiments are summarized in Tables 2-6.TABLE 2 Relative Tissue or Cell Type Expression Normal Artery 0.2 NormalVein 0.8 Early Aortic Smooth Muscle Cells 7.2 Coronary Smooth MuscleCells 14.3 Static Human Umbilical Vascular Epithelial Cells 8.3 ShearHuman Umbilical Vascular Epithelial Cells 8.4 Normal Heart 2.2 HeartCongestive Heart Failure 3.4 Kidney 6.4 Skeletal Muscle 1.7 NormalAdipose 0.4 Pancreas 3.2 Primary Osteoblasts 1.4 DifferentiatedOsteoclasts 0.2 Normal Skin 3.2 Normal Spinal cord 4.9 Normal BrainCortex 128 Normal Brain Hypothalamus 32.0 Nerve 3.9 Dorsal Root Ganglion9.3 Glial Cells (Astrocytes) 31.9 Glioblastoma 2.5 Normal Breast 1.2Breast Tumor 5.3 Normal Ovary 21.9 Ovary Tumor 2.9 Normal Prostate 2.0Prostate Tumor 2.7 Prostate Epithelial Cells 6.8 Normal Colon 0.6 ColonTumor 3.8 Normal Lung 0.7 Lung Tumor 5.2 Chronic Obstructive PulmonaryDisease Lung 1.7 Inflammatory Bowel Disease Colon 0.8 Normal Liver 1.4Liver fibrosis 4.3 Dermal Cells - fibroblasts 4.3 Normal Spleen 2.7Normal Tonsil 3.9 Lymph node 9.5 Resting Peripheral Blood MononuclearCells 1.0 Skin-Decubitus 5.9 Synovium 1.8 Bone marrow mononuclear cells2.8 Activated Peripheral Blood Mononuclear Cells 3.0

[0053] TABLE 3 Relative Tissue or Cell Type Expression Lung MPI 188 1Kidney 9 Spleen 3 Fetal Liver MPI BMW54 17 Grans #9 3 NHDF Mock 1 NHLFMock 4 NHLF TGF 5 NC Heps 2 Pass Stell 2 Liver LF NDR 200 0 Liver LF NDR191 1 Lymph Nodes 11 Tonsils 3 TH0 046 6 hr 3 TH1 046 6 hr 5 TH2 046 6hr 3 CD8 6 CD14 0 CD19 2 CD3 Resting 3 MBM MNC LP139 1 mPB CD34+ LP152 1Bone Marrow CD34+ LP154 1 Cord Blood CD34+ LP121 2 Erythroid 32 Meg 3Neut d 14 1 Bone Marrow CD15+ CD14− LP32 0 mBM CD15+ CD11b− 0 BoneMarrow GPA+ 14 K562 7 HL60 6 Molt4 22 Normal Hep3b 3 Hep3b Hyp 8

[0054] TABLE 4 Relative Tissue or Cell Type Expression Brain 8.7 BrainCortex 18.2 Breast 0.7 Colon Tumor 0.5 Heart 2.0 Kidney 1.3 Normal Liver0.4 Liver fib 0.5 Lung Tumor 1.2 Ovary 2.4 mBM CD34+ LP92 1.3 mBM CD34+LP143 1.2 mPB CD34+ LF70 1.2 mPB CD34+ LF162 1.1 Bone Marrow CD34+ LF930.4 Bone Marrow CD34+ LP154 2.0 Cord Blood CD34+ LP121 1.7 Cord BloodCD34+LF101 2.1 GPA+ High LP34−1 9.8 GPA+ High 9.5 GPA+ High 69 5.6 GPA+High 74 3.2 GPA+ Low LP69 5.4 GPA+ Low LP82 3.6 In Vitro Erythroid 24hours LF102 3.9 In Vitro Erythroid 48 hours LF87 2.7 In Vitro Erythroid48 hours LF102 4.0 In Vitro Erythroid 48 hours LF72 7.6 In VitroErythroid day 6 LP31−1 7.8 In Vitro Erythroid day 6 LF113 21.1 In VitroErythroid day 7 LF24−5 13.6 In Vitro Erythroid day 8 LF113 24.2 In VitroErythroid day 10 LP24−4 16.0 In Vitro Erythroid day 12 LF23−8 13.1 InVitro Erythroid day 12 LF24−10 13.0 In Vitro Erythroid day 12 LF113 13.5In Vitro Erythroid day 14 GPA+ LP31−4 3.7 In Vitro Burst-Forming Unitday 7 LP79 10.6 In Vitro Burst-Forming Unit day 7 LP95 10.9 In VitroBurst-Forming Unit day 7 + 3 days 10.9 Erythropoietin LP81 In VitroBurst-Forming Unit day 7 + 3 days 15.6 Erythropoietin LP104

[0055] TABLE 5 Relative Tissue or Cell Type Expression Lung 2 Colon MPI60 2 Spleen MPI 380 4 Kidney MPI 58 2 Liver NDR 200 0 Fetal Liver MPI133 31 Sk Muscle MPI 167 2 mBM MNC LP140 2 mBM MNC LP7 0 mBM CD34+ LP924 mBM CD34+ LP143 2 mPB CD34+ LF70 1 mPB CD34+ LP162 1 Bone Marrow CD34+LF93 1 Bone Marrow CD34+ LP154 2 Cord Blood CD34+ LP163 3 Cord BloodCD34+ LP101 2 Bone Marrow GPA+ LF74 4 Bone Marrow GPA+ LP34−1 18 BoneMarrow GPA^(LOW) LP69 5 Bone Marrow GPA^(LOW) LP82 6 mPB CD41+ CD14−LP119 0 Bone Marrow CD41+ CD14− LP132 1 mBM CD15+ LP15 0 mBM CD15+CD11b− LF120 0 mBM CD15+ CD11b+ LP15−2 0 Bone Marrow CD15+ CD11b− LF80−41 Bone Marrow CD15+ CD11b− LP23−2 0 Bone Marrow CD15+ CD11b− LF128 1Bone Marrow CD15+ CD11b+ LF128 0 Bone Marrow CD15+ CD34− LP27−2 0 BoneMarrow CD15+ CD34− LP41−1 0

[0056] TABLE 6 Relative Tissue or Cell Type Expression In VitroErythroid 24 hours LF102 2 In Vitro Erythroid 48 hours LF73 4 In VitroErythroid 48 hours LF87 2 In Vitro Erythroid 48 hours LF90 2 In VitroErythroid 48 hours LF102 3 In Vitro Erythroid day 6 LP31−1 7 In VitroErythroid day 6 LF113 16 In Vitro Erythroid day 7 LF24−5 10 In VitroErythroid day 8 LF113 20 In Vitro Erythroid day 10 LP24−4 9 In VitroErythroid day 12 LF23−8 13 In Vitro Erythroid day 12 LF24−10 15 In VitroErythroid day 12 LF113 9 In Vitro Erythroid day 14 GPA+ LP31−4 2 Megs 24hr LF102 3 Megs 48 hr LF102 3 Meg d 6 LF110 2 Meg d 7 LP31−2 2 Meg d 10LF110 2 Meg d 12 LF102 1 Meg d 12 LF35 1 Meg d 14 LP31−5 2 Neutrophils d4 LF71 2 Neutrophils d 4 LF78 1 Neutrophils d 6 LF26 1 Neutrophils d 6LP71 1 Neutrophils d 6 LP78 2 Neutrophils d 7 LP41−3 1 Neutrophils d 8LF78 1 Neutrophils d 11 LF78 3 Neutrophils d 12 LP26B 1 Neutrophils d 13LF78 3 Neutrophils d 14 LF71 1 Neutrophils d 14 LF78 1 Neutrophils d 14LP31−6 0 Platelets 0 Mast cells LP71 3 Mast Cells LP118 4 Burst-FormingUnits day 7 LP79 12 Burst-Forming Units day 7 LP95 12 Burst-FormingUnits day 7+ 3 days Erythropoietin 15 LP81 Burst-Forming Units day 7+ 3days Erythropoietin 18 LP104

[0057] Human 18080

[0058] Nucleotide and corresponding amino acid sequences for a serinecarboxypeptidase family member, referred to herein as “18080” aredisclosed. 18080 protein is identical in sequence to Genbank AccessionNo. AF282618_(—)1. Applicants have shown expression of 18080 mRNA inhuman hematopoietic cells, e.g., erythroid cells, as well as, adrenalglands and endothelial cells. Accordingly, modulators of 18080polypeptide activity or expression may be used to treat or preventhematopoietic and angiogenic disorders.

[0059] The human 18080 sequence (SEQ ID NO: 11), which is approximately1921 nucleotides long including untranslated regions, contains apredicted methionine-initiated coding sequence of about 1356 nucleotides(nucleotides 33-1388 of SEQ ID NO: 11; 1-1356 of SEQ ID NO: 13), notincluding the terminal codon. The coding sequence encodes a 452 aminoacid protein (SEQ ID NO: 12).

[0060] The human 18080 protein of SEQ ID NO: 12 includes anamino-terminal hydrophobic amino acid sequence, consistent with a signalsequence, of about 27 amino acids (from amino acid 1 to about amino acid27 of SEQ ID NO: 12), which upon cleavage results in the production of amature protein form. This mature protein form is approximately 425 aminoacid residues in length (from about amino acid 28 to amino acid 452 ofSEQ ID NO: 12).

[0061] The serine carboxypeptidase domain of human 18080 was alignedwith a consensus amino acid sequence derived from a hidden Markov model(HMM) from PFAM. The algorithm identified two local alignments betweenthe consensus amino acid sequence and human 18080. Two consensus aminoacid sequences (SEQ ID NOs: 14 and 15), aligned to amino acids 42 to 236and 337 to 451 of SEQ ID NO: 12.

[0062] Human 18080 contains the following regions or other structuralfeatures: a serine carboxypeptidase domain (PROSITE Accession NumberPDOC00122) including a serine carboxypeptidase-serine active site(PS00131) and a serine carboxypeptidase-histidine active site (PS00560)located at about amino acid residues 42 to 236 and 337 to 451 of SEQ IDNO: 12, respectively; three predicted N-glycosylation sites (PS00001)located at about amino acids 64 to 67, 126 to 129, and 362 to 365 of SEQID NO: 12; one predicted cAMP/cGMP-dependent protein kinasephosphorylation sites (PS00004) located at about amino acids 101 to 104of SEQ ID NO: 12; four predicted Protein Kinase C phosphorylation sites(PS00005) located at about amino acids 44 to 46, 61 to 63, 188 to 190,and 417 to 419 of SEQ ID NO: 12; six predicted Casein Kinase IIphosphorylation sites (PS00006) located at about amino acids 204 to 207,220 to 223, 280 to 283, 284 to 287, 351 to 354, and 449 to 452 of SEQ IDNO: 12; and eight predicted N-myristylation sites (PS00008) located atabout amino acids 22 to 27, 76 to 81, 119 to 124, 169 to 174, 187 to192, 195 to 200, 331 to 336, and 360 to 365 of SEQ ID NO: 12.

[0063] For general information regarding PFAM identifiers, PS prefix andPF prefix domain identification numbers, refer to Sonnhammer et al.(1997) Protein 28:405-420.

[0064] Proteolytic enzymes that exploit serine in their catalyticactivity are ubiquitous, being found in viruses, bacteria, andeukaryotes. See, e.g., Rawlings & Barrett (1994) Methods Enzymol. 244:19-61. Over 20 families of serine peptidase have been identified, thesebeing grouped into 6 clans on the basis of structural similarity andother functional evidence. Structures are known for 4 of the clans:these appear to be totally unrelated, suggesting at least fourevolutionary origins of serine peptidases. Their different evolutionaryorigins notwithstanding, there are similarities in the reactionmechanisms of several peptidases. Carboxypeptidase C family, likechymotrypsin and subtilisin, has a catalytic triad of serine (S),aspartate (D), and histidine (H): serine acts as a nucleophile,aspartate as an electrophile, and histidine as a base. See, e.g.,Rawlings & Barrett (1994) Biochem. J. 290: 205-218.

[0065] Carboxypeptidase C includes a number of serine carboxypeptidases,which are unusual in that their optimum activity occurs in acidicconditions. In higher organisms, serine carboxypeptidases areglycoproteins (for reviews, see Breddam (1986) Carlsberg Res. Commun.51: 83-128), and hydrolyze COOH-terminal peptide bonds. In humans, ahighly specific serine carboxypeptidase cleaves the COOH-terminalresidue of angiotensin II and III, and may be involved in the regulationof blood pressure. See, e.g., Odya et al. (1978) J. Biol. Chem. 253:5927-5931 and Odya & Erdos (1981) Methods Enzymol. 80: 460-466. Inaddition, serine carboxypeptidases may be involved in degrading growthfactors or extracellular matrix.

[0066] The 18080 protein contains a significant number of structuralcharacteristics in common with members of the serine carboxypeptidasefamily. Serine carboxypeptidase family members are characterized by acommon catalytic mechanism which is provided by a charge relay systeminvolving an aspartic acid residue hydrogen-bonded to a histidine, whichis itself hydrogen-bonded to a serine. The catalytic triad catalyzes ahydrolysis reaction involving a COOH-terminal peptide bond. A serinecarboxypeptidase family of proteins has two signature motifs—one motifincludes the residues of [LIVM]-x-[GTA]-E-S—Y-[AG]-[GS] (SEQ ID NO: 16),which contains the catalytic serine (S) and one motif spans the regionencoded by[LIVF]-x(2)-[LIVSTA]-x-[IVPST]-x-[GSDNQL]-[SAGV]-[SG]-H-x-[IVAQ]-P-x(3)-[PSA](SEQ ID NO: 17), which contains the catalytic histidine (H). Residuescorresponding to catalytic serine and histidine residues are located atamino acids 167 and 431 of SEQ ID NO: 12, respectively. The amino acidsequence of 18080 is identical to the sequence of a serinecarboxypeptidase 1 precursor protein having Genbank's accession numberAAG16692 (AF282618).

[0067] As used herein, the term “serine carboxypeptidase domain”includes an amino acid sequence of about 50 to 500 amino acid residuesin length, more preferably about 70 to 400 amino acid residues, or about100 to 350 amino acids and has a bit score for the alignment of thesequence to the serine carboxypeptidase domain (HMM) of at least 70 orgreater. Preferably, the domain includes one motif: IFSESYGG (SEQ ID NO:18) located at about amino acids 163 to 170 of SEQ ID NO: 12, whichincludes the catalytic serine (located at amino acid 167 of SEQ ID NO:12), and another motif: LAFYWILKAGHMVP (SEQ ID NO: 19) located at aboutamino acids 421 to 434 of SEQ ID NO: 12, which includes the catalytichistidine (located at amino acid 431 of SEQ ID NO: 12). The serinecarboxypeptidase motif including a catalytic serine (HMM) has beenassigned the PFAM Accession Number PF00131, and the serinecarboxypeptidase motif including a catalytic histidine (HMM) has beenassigned the PFAM Accession Number PF00560. The serine carboxypeptidasedomain (amino acids 42 to 236 and 337 to 451 of SEQ ID NO: 12) of human18080 aligns with a consensus amino acid sequence derived from a hiddenMarkov model derived from PFAM.

[0068] In a preferred embodiment 18080 polypeptide or protein has a“serine carboxypeptidase domain” or a region which includes at leastabout 50 to 500 more preferably about 70 to 400, or 100 to 350 aminoacid residues and has at least about 50%, 60%, 70% 80% 90% 95%, 99%, or100% homology with a “serine carboxypeptidase domain,” e.g., the serinecarboxypeptidase domain of human 18080 (e.g., residues 42 to 236 and 337to 451 of SEQ ID NO: 12).

[0069] In a hydropathy plot of human 18080, polypeptides of theinvention include fragments which include: all or part of a hydrophobicsequence, e.g., the sequence from about amino acid 135 to 152 of SEQ IDNO: 12; and all or part of a hydrophilic sequence, e.g., the sequence offrom about amino acid 93 to 108 of SEQ ID NO: 12.

[0070] To identify the presence of a “serine carboxypeptidase” domain ina 18080 protein sequence, and make the determination that a polypeptideor protein of interest has a particular profile, the amino acid sequenceof the protein can be searched against the Pfam database of HMMs (e.g.,the Pfam database, release 2.1) using the default parameters. Forexample, the hmmsf program, which is available as part of the HMMERpackage of search programs, is a family specific default program forMILPAT0063 and a score of 15 is the default threshold score fordetermining a hit. Alternatively, the threshold score for determining ahit can be lowered (e.g., to 8 bits). A description of the Pfam databasecan be found in Sonhammer et al. (1997) Proteins 28(3): 405-420 and adetailed description of HMMs can be found, for example, in Gribskov etal.(1990) Meth. Enzymol. 183:146-159; Gribskov et al.(1987) Proc. Natl.Acad. Sci. USA 84:4355-4358; Krogh et al.(1994) J. Mol. Biol.235:1501-1531; and Stultz et al.(1993) Protein Sci. 2:305-314, thecontents of which are incorporated herein by reference. A search wasperformed against the HMM database resulting in the identification oftwo “serine carboxypeptidase” domains in the amino acid sequence ofhuman 18080 at about residues 42 to 236 and 337 to 451 of SEQ ID NO: 12.

[0071] A 18080 protein can further include a signal peptide, and ispredicted to be a secreted protein. As used herein, a “signal peptide”or “signal sequence” refers to a peptide of about 10 to 40, preferablyabout 15 to 30, more preferably, about 27 amino acid residues in lengthwhich occurs at the N-terminus of secretory and integral membraneproteins and which contains a majority of hydrophobic amino acidresidues. For example, a signal sequence contains at least about 10 to40, preferably about 15 to 30, more preferably, 27 amino acid residues,and has at least about 40-70%, preferably about 50-65%, and morepreferably about 55-60% hydrophobic amino acid residues (e.g., alanine,valine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan, orproline). Such a “signal sequence”, also referred to in the art as a“signal peptide,” serves to direct a protein containing such a sequenceto a lipid bilayer. For example, in one embodiment, a 18080 proteincontains a signal sequence of about amino acids 1 to 27 of SEQ ID NO:12. The “signal sequence” is cleaved during processing of the matureprotein. The mature 18080 protein corresponds to amino acids 28 to 452of SEQ ID NO: 12.

[0072] A 18080 family member can include a “serine carboxypeptidasedomain” or regions homologous with a “serine carboxypeptidase domain.” A18080 polypeptide can optionally further include at least one, two,preferably three N-glycosylation sites (PS0001); at least one cAMP- andcGMP-dependent protein kinase phosphorylation site (PS0004); at leastone, two, three, preferably four protein kinase C phosphorylation sites(PS0005); at least one, two, three, four, five, preferably six caseinkinase II phosphorylation sites (PS0006); and at least one, two, three,four, five, six, seven, preferably eight N-myristylation sites (PS0008).

[0073] Based on the above-described sequence similarities and the tissuedistribution described below, the 18080 molecules of the presentinvention are predicted to have similar biological activities as serinecarboxypeptidase family members. Thus, in accordance with the invention,a 18080 serine carboxypeptidase or subsequence or variant polypeptidemay have one or more domains and, therefore, one or more activities orfunctions characteristic of a serine carboxypeptidase family member,including, but not limited to: (1) modulating removal of COOH-terminalresidues, i.e., having carboxypeptidase activity; (2) modulating thetransfer of an acyl group from a donor to an acceptor molecule, i.e.,having acyltransferase activity; (3) modulating (e.g., stimulating) celldifferentiation, e.g., differentiation of hematopoietic cells (e.g.,differentiation of blood cells (e.g., erythroid progenitor cells, suchas CD34+ erythroid progenitors)); (4) modulating hematopoiesis, e.g.,erythropoiesis; (5) modulating cell proliferation, e.g., proliferationof hematopoietic cells (e.g., erythroid progenitor cells); (6)modulating apoptosis, of a cell, e.g., increase apoptosis of a cancercell, e.g., a leukemic cell, (e.g., an erythroleukemia cell); orsuppress apoptosis of a blood or erythroid cell; or (7) modulatingerythroid progenitors by allowing greater interaction with growthfactors or extracellular matrix.

[0074] As the 18080 polypeptides of the invention may modulate18080-mediated activities, they may be useful as of for developing noveldiagnostic and therapeutic agents for 18080-mediated or relateddisorders, as described below.

[0075] As used herein, a “18080 activity”, “biological activity of18080” or “functional activity of 18080”, refers to an activity exertedby a 18080 protein, polypeptide or nucleic acid molecule. For example, a18080 activity can be an activity exerted by 18080 in a physiologicalmilieu on, e.g., a 18080-responsive cell or on a 18080 substrate, e.g.,a protein substrate. A 18080 activity can be determined in vivo or invitro. In one embodiment, a 18080 activity is a direct activity, such asan association with a 32229 target molecule. A “target molecule” or“binding partner” is a molecule with which a 18080 protein binds orinteracts in nature. In an exemplary embodiment, 18080 is an enzyme forpeptide or protein substrate. In other embodiments, an 18080 hasacyltransferase activity.

[0076] 18080 mRNA is found primarily in hematopoietic progenitor cells(Tables 7-11). High levels of 18080 mRNA expression were observed inerythroid cells. Its expression is further enhanced in the erythroidlineage and increases as bone marrow/blood cell differentiationproceeds. High levels of 18080 mRNA expression were also detected inadrenal glands and human umbilical vein endothelial cells (HUVECS).Tables 8-11 show TaqMan assays on mRNA most derived from humanhematological samples, e.g., bone marrow (BM), erythroid cells (Eryth),megakaryocytes (Meg), neutrophils (Neut), or a negative reference sample(NTC). In Table 8, 18080 mRNA was highly expressed in BM glycophorin A(GPA) positive cells, followed by mBM CD34+ cells and Eryth cells. InTable 9, 18080 mRNA expression was observed in GPA Hi/Lo LF 156 Erythcells, GPA Hi/Lo LF154 Eryth cells, and Kidney cells. In Table 10, mRNAexpression was detected at the indicated times in culture (e.g., 24 hrs,48 hrs, 6 days (D6), 12 days (D12). High levels of 18080 expressionswere observed in one sample of Eryth LF127 cells and in one sample ofEryth LF139 cells, especially day 6 and day 12, respectively. In Table11, mRNA expression was detected at the indicated times in culture(e.g., 24 hrs., 48 hrs., days in culture). Moderate level of 18080 mRNAexpressions were observed in Meg LF 157 cells and Neut LF141 cells,especially day 10 and day 6, respecitively.

[0077] Significant expression of 18080 mRNA is found in the bone marrow,cord blood, fetal liver, and in particular, in glycophorin A-expressing(GPA) cells or CD34-expressing populations of cells from those tissues,such as mobilized peripheral blood GPA+/CD34+ cells, normal adult bonemarrow GPA+/CD34+ cells, cord blood GPA+/CD34+ cells, normal adult bonemarrow GPA+/CD34+ cells, and fetal liver GPA+/CD34+ cells; as well aserythroid progenitor cells, e.g., erythropoietin treated erythroid burstforming units (BFUs), erythrocytes, in vitro generated erythroblasts,and megakaryocytes (Tables 7-8). Thus, diagnostic and therapeuticmethods using the molecules of the invention (or agents that modulatethe activity or expression of the 18080 molecules) to treat/diagnosedisorders involving the cells/tissues expressing 18080 molecules arecontemplated by the present invention. Inhibition of the 18080 moleculeswill likely stimulate erythroid progenitors by allowing greaterinteraction with growth factors or extracellular matrix.

[0078] As used herein, a “glycophorin A-positive cell” or a “glycophorinA-expressing cell-cell” refers to a cell that expresses detectablelevels of the glycophorin A antigen, preferably human glycophorin Aantigen. Glycophorin A is a 31 kD erythrocyte membrane glycoprotein, andis typically present on immature hematopoietic precursor cells andhematopoietic colony-forming cells in the bone marrow.

[0079] As used herein, a “CD34-positive cell” or a “CD34-expressingcell” refers to a cell that expresses detectable levels of the CD34antigen, preferably human CD34 antigen. The sequence for human CD34 isprovided in SwissProt Accession Number P28906. The CD34 antigen istypically present on immature hematopoietic precursor cells andhematopoietic colony-forming cells in the bone marrow, includingunipotent (CFU-GM, BFU-E) and pluripotent progenitors (CFU-GEMM, CFU-Mixand CFU-blast). The CD34 is also expressed on stromal cell precursors.Terminal deoxynucleotidyl transferase (TdT)-positive B- and T-lymphoidprecursors in normal bone also are CD34+. The CD34 antigen is typicallypresent on early myeloid cells that express the CD33 antigen, but lackthe CD14 and CD15 antigens and on early erythroid cells that express theCD71 antigen and dimly express the CD45 antigen. The CD34 antigen isalso found on capillary endothelial cells and approximately 1% of humanthymocytes. Normal peripheral blood lymphocytes, monocytes, granulocytesand platelets do not express the CD34 antigen. CD34 antigen density ishighest on early hematopoietic progenitor cells and decreases as thecells mature. The antigen is undetectably on fully differentiatedhematopoietic cells. Approximately 60% of acute B-lymphoid leukemia'sand acute myeloid leukemia express the CD34 antigen. The antigen is notexpressed on chronic lymphoid leukemia (B or T lineage) or lymphomas.

[0080] As the 18080 polypeptides of the invention may modulate18080-mediated activities, they may be useful as of for developing noveldiagnostic and therapeutic agents for 18080-mediated or relateddisorders, e.g., hematopoeitic disorder (e.g., blood cell- (e.g.,erythroid-) associated disorders), endothelial cell disorders,cardiovascular disorders, as well as angiogenic disorders (e.g.,cancerous disorders and/or disorders involving aberrant tumor growth).

[0081] Agents that modulate 18080 polypeptide or nucleic acid activityor expression can be used to treat anemias, in particular, drug-inducedanemias or anemias associated with cancer chemotherapy, chronic renalfailure, malignancies, adult and juvenile rheumatoid arthritis,disorders of hemoglobin synthesis, prematurity, and zidovudine treatmentof HIV infection. A subject receiving the treatment can be additionallytreated with a second agent, e.g., erythropoietin, to further amelioratethe condition.

[0082] As used herein, the term “erythropoietin” or “EPO” refers to aglycoprotein produced in the kidney, which is the principal hormoneresponsible for stimulating red blood cell production (erythrogenesis).EPO stimulates the division and differentiation of committed erythroidprogenitors in the bone marrow. Normal plasma erythropoietin levelsrange from 0.01 to 0.03 Units/mL, and can increase up to 100 to1,000-fold during hypoxia or anemia. Graber and Krantz, Ann. Rev. Med.29:51 (1978); Eschbach and Adamson, Kidney Intl. 28:1 (1985).Recombinant human erythropoietin (rHuEpo or epoietin alpha) iscommercially available as EPOGEN.RTM. (epoietin alpha, recombinant humanerythropoietin) (Amgen Inc., Thousand Oaks, Calif.) and as PROCRIT.RTM.(epoietin alpha, recombinant human erythropoietin) (Ortho Biotech Inc.,Raritan, N.J.).

[0083] Another example of an erythroid-associated disorder iserythrocytosis. Erythrocytosis, a disorder of red blood celloverproduction caused by excessive and/or ectopic erythropoietinproduction, can be caused by cancers, e.g., a renal cell cancer, ahepatocarcinoma, and a central nervous system cancer. Diseasesassociated with erythrocytosis include polycythemias, e.g., polycythemiavera, secondary polycythemia, and relative polycythemia.

[0084] Since 18080 mRNA is expressed in endothelial cells, molecules ofthe incention can be used as therapeutic and diagnostic target to treatenodothelial cell related disorders, e.g., cardiovascular (e.g., bloodvessel or hematological disorders), and angiogenic disorders, e.g.,cancers or disorders involving tumor growth.

[0085] Aberrant expression or activity of the 18080 molecules may beinvolved in neoplastic disorders. Accordingly, treatment, prevention anddiagnosis of cancer or neoplastic disorders related to hematopoieticcells and, in particular, cells of the erythroid lineage are alsoincluded in the present invention. Such neoplastic disorders areexemplified by erythroid leukemias, or leukemias of erythroid precursorcells, e.g., poorly differentiated acute leukemias such aserythroblastic leukemia and acute megakaryoblastic leukemia. Additionalexemplary myeloid disorders include, but are not limited to, acutepromyeloid leukemia (APML), acute myelogenous leukemia (AML) and chronicmyelogenous leukemia (CML) (reviewed in Vaickus, L. (1991) Crit Rev. inOncol./Hemotol. 11:267-97). In particular, AML can include theuncontrolled proliferation of CD34+ cells such as AML subtypes M1 andM2, myeloblastic leukemias with and without maturation, and AML subtypeM6, erythroleukemia (Di Guglielmo's disease). Additional neoplasticdisorders include a myelodysplastic syndrome or preleukemic disorder,e.g., oligoblastic leukemia, smoldering leukemia. Additional cancers ofthe erythroid lineage include erythroblastosis, and other relevantdiseases of the bone marrow.

[0086] The molecules of the invention may also modulate the activity ofneoplastic, non-hematopoietic tissues. Accordingly, the 18080 moleculescan act as novel diagnostic targets and therapeutic agents forcontrolling one or more of cellular proliferative and/or differentiativedisorders. Examples of such cellular proliferative and/ordifferentiative disorders include cancer, e.g., carcinoma, sarcoma, ormetastatic disorders. A metastatic tumor can arise from a multitude ofprimary tumor types, including but not limited to those of lung,prostate, colon, breast, and liver origin.

[0087] Gene Expression of 18080

[0088] Table 7 depicts relative 18080 mRNA expression as determined byTaqMan assays in a panel of human tissues, including artery normal,aorta diseased, vein normal, coronary SMC, Human Umbilical VeinEndothelial Cells (HUVEC), heart, pancreas, skin, spinal cord, brain,adrenal glands, dorsal root gland (DRG), nerve, breast, ovary, colon,lung, liver, megakaryocytes, and erythroid. The highest 18080 mRNAexpression was observed in erythroid, followed by adrenal glands andHUVEC cells. Moderate 18080 mRNA expression was observed in most of theother tissues

[0089] Tables 8-11 depicts relative 18080 mRNA expression as determinedby TaqMan assays on mRNA most derived from human hematological samples,e.g., bone marrow (BM), erythroid cells (Eryth), megakaryocytes (Meg),neutrophils (Neut), or a negative reference sample (NTC). In Table 8,18080 mRNA was highly expressed in BM glycophorin A (GPA) positivecells, followed by mBM CD34+ cells and erythroid cells. In Table 9,18080 mRNA expression was observed in GPA Hi/Lo LF 156 Eryth cells, GPAHi/Lo LF154 erythroid cells, and kidney cells. In Table 10, mRNAexpression was detected at the indicated times in culture (e.g., 24 hrs,48 hrs, 6 days (D6), 12 days (D12). High levels of 18080 expressionswere observed in one sample of Eryth LF127 cells and in one sample ofEryth LF139 cells, especially day 6 and day 12, respectively. In Table11, 18080 mRNA expression was detected at the indicated times in culture(e.g., 24 hrs., 48 hrs., days in culture). Moderate levels of 18080 mRNAexpressions were observed in Meg LF 157 cells and Neut LF141 cells,especially day 10 and day 6, respecitively. The relative tissuedistribution of 18080 mRNA is depicted in tabular form in Tables 8-11.TABLE 7 Tissue Type Mean β 2 Mean ∂∂ Ct Expression Artery normal 27 21 618 Aorta diseased 29 23 6 16 Vein normal 27 20 7 10 Coronary SMC 28 21 612 HUVEC 26 21 5 33 Hemangioma 29 21 8 3 Heart normal 27 21 7 11 HeartCHF 28 21 6 12 Kidney 27 21 6 15 Skeletal Muscle 30 23 7 7 Liver normal30 20 10 1 Small intestine normal 31 21 10 1 Adipose normal 28 20 8 5Pancreas 31 23 9 3 primary osteoblasts 28 20 8 4 Bladder-Female normal28 20 8 5 Adrenal Gland normal 25 20 5 30 Pituitary Gland normal 28 21 85 Brain Cortex normal 30 23 6 13 Brain Hypothalamus normal 29 22 7 6Nerve 29 21 7 6 DRG (Dorsal Root Ganglion) 29 22 8 5 Breast normal 27 216 17 Breast tumor/IDC 29 20 8 3 Ovary normal 28 21 8 5 Ovary Tumor 27 216 11 Prostate BPH 27 20 7 11 Prostate Adenocarcinoma 28 21 7 7 Colonnormal 28 20 8 4 Colon Adenocarcinoma 30 22 8 5 Lung normal 27 19 8 4Lung tumor 28 22 6 13 Lung COPD 26 19 7 6 Colon IBD 32 21 11 1 Synovium29 20 9 2 Tonsil normal 28 19 8 3 Lymph node normal 29 21 8 3 Liverfibrosis 31 22 9 2 Spleen normal 29 19 10 1 Macrophages 25 18 7 7Progenitors (erythroid, mega- 29 20 8 3 karyocyte, neutrophil)Megakaryocytes 28 20 7 6 Activated PBMC 30 17 13 0 Neutrophils 30 19 111 Erythroid 27 22 5 32 positive control 28 22 6 12

[0090] TABLE 8 18080 B2 relative exp. lung 24 18 24 kidney 23 19 53spleen 26 20 14 fetal liver 29 24 31 grans. 28 21 9 NHDF mock 24 18 22NHDF TGF 24 19 31 NHLF mock 24 19 22 NHLF TGF 24 18 23 NC Heps 27 20 6Pass. Stel. 24 18 21 liver 27 20 8 NDR200 29 22 7 NDR191 27 21 14 NDR07925 20 30 lymph node 25 18 10 tonsil 24 19 22 Th0 27 17 1 Th1 27 17 1 Th227 17 1 CD4 29 21 3 CD8 26 18 4 CD14 22 17 32 CD19 27 20 8 CD3 27 18 2mBM CD34+ 23 18 42 mPB CD34+ 27 19 3 BM CD34+ 26 20 15 Cord Blood 27 194 Ery. 22 18 42 Megs. 27 21 19 neut. 26 19 5 CD15+14− 22 17 20 mBMCD15+11b− 23 18 22 BM GPA+ 25 22 132 K562 25 20 26 HL60 23 18 36 molt 2520 18 Hep36norm 25 20 37 Hep36 Hyp 25 21 45 NTC 40 40

[0091] TABLE 9 18080 Beta Rel exp Lung CHT 330 28 22 12 Heart PT 262 2922 9 Spleen 380 27 20 5 Kidney 27 25 21 58 Liver NDR 379 30 22 3 FetalLiver BWH 54 29 22 7 Brain MCL 400 27 21 16 Colon PIT 259 28 21 7 MusclePIT 284 30 23 7 mBM MNC LP7 25 19 13 mBM CD34+ LP92 28 20 5 mPB CD34+LP350 30 20 1 mPB CD34+ LF53 26 20 16 BM CD34+ LF89 27 19 6 BM CD34+LF75 26 19 12 Cord Blood CD34+ MF1 29 22 5 Cord Blood CD34+ LF101 27 193 GPA Hi LF154 27 22 39 GPA Hi LF156 26 21 20 GPA Lo LF154 26 21 31 GPALo LF156 27 21 25 MF11 Stromal D 32 post irrad 25 19 13 MF12 Stromalcntl 24 18 12 MF13 Stromal D 2 post irrad 24 17 8

[0092] TABLE 10 18080 Beta Rel exp mBM CD61+ LP196 26 21 26 PlateletsLP57 39 22 0 mBM CD14−/11b−/15+ LF120 25 19 21 BM CD14−/11b−/15+ LF54 2520 25 BM CD14−/11b−/15+ LF128 26 19 6 BM CD14−/11b−/15+ LF145 25 20 16mBM CD14−/11b+/15+ LF120 26 20 11 BM CD14−/11b+/15+ LF106 25 19 23 BMCD11b+/15+ LF128 26 20 19 BM−1 CD15+ ench LP41 26 20 16 Eryth D 0 LF12730 20 2 Eryth 48 hr LF127 31 24 5 Eryth D 6 LF127 26 22 97 Eryth D 12LF127 27 21 21 Eryth D 0 LF139 31 22 1 Eryth 24 hr LF139 32 23 1 Eryth48 hr LF139 30 21 2 Eryth D 6 LF139 27 22 26 Eryth D 12 LF139 26 22 47BFU Eryth D 7 LP79 27 21 17 BFU Eryth D 7 LP95 28 21 14 BFU Eryth D 7 +3epo LP81 28 21 11 BFU Eryth D 7 +3 epo LP104 27 22 17 Mast Cell LP118 2721 20

[0093] TABLE 11 18080 Beta Rel exp Meg D 0 LF140 28 20 4 Meg 48 hr LF14029 20 2 Meg D 6 LF140 27 20 7 Meg D 12 LF140 26 20 9 Meg 24 hr LF102 3020 1 Meg 48 hr LF102 29 20 2 Meg 48 hr LF110 31 21 1 Meg D 9 LP127 27 206 Meg D 10 LF110 27 19 6 Meg D 12 LF26 27 21 10 Meg 24 hr LF157 30 20 2Meg 48 hr LF157 29 20 2 Meg D 6 LF157 27 19 6 Meg D 10 LF157 26 20 14Meg D 0 LF166 29 19 1 Meg 24 hr LF166 30 19 1 Meg 48 hr LF166 30 20 1Meg D 6 LF166 28 20 4 Meg D 10 LF166 27 20 6 Neut D 0 LF141 27 19 4 Neut48 hr LF141 27 19 5 Neut D 6 LF141 26 19 10 Neut D 12 LF141 25 18 7 NeutD 0 LF144 29 22 7 Neut 48 hr LF144 26 19 11 Neut D 6 LF144 28 21 5 NeutD 12 LF144 28 21 8 NTC 40 40

[0094] Human 14081

[0095] The present invention is based, in part, on the discovery of aserine protease, referred to herein as “14081”. The transporter moleculeof the invention shares characteristics with members of the trypsin-likefamily of serine proteases.

[0096] The human 14081 sequence (SEQ ID NO: 20), which is approximately980 nucleotides long including untranslated regions, contains apredicted methionine-initiated coding sequence of about 780 nucleotides,not including the termination codon (nucleotides 18-797 of SEQ ID NO:20; 1-780 of SEQ ID NO: 22). The coding sequence encodes a 260 aminoacid protein (SEQ ID NO: 21).

[0097] Human 14081 contains the following regions or other structuralfeatures (for general information regarding PFAM identifiers, PS prefixand PF prefix domain identification numbers, refer to Sonnhammer et al.(1997) Protein 28:405-420 and a trypsin-like domain located at aboutamino acid nucleotides 4 to 242 of SEQ ID NO: 21; two transmembranedomains (predicted 106 to 122 and 203 to 219 of SEQ ID NO: 21; twoprotein kinase C phosphorylation sites (Prosite PS00005) located atabout amino acids 158 to 160, and 177 to 179 of SEQ ID NO: 21; threecasein kinase II phosphorylation sites (Prosite PS00006) located atabout amino acids 91 to 94, 135 to 138, and 218 to 221 of SEQ ID NO: 21;two N-glycosylation sites (Prosite PS00001) located at about amino acids25 to 28 and 49 to 52 of SEQ ID NO: 21; and four N-myristoylation sites(Prosite PS00008) located at about amino acids 7 to 12, 26 to 31, 32 to37, and 88 to 93 of SEQ ID NO: 21.

[0098] A hydropathy plot of human 14081 was performed. Polypeptides ofthe invention include fragments which include: all or part of ahydrophobic sequence, e.g., the sequence from about amino acid 25 to 45(a sequence that includes a glycosylation site at position 24 to 28),from about 52 to 62, from about 91 to 122, and from about 203 to 219 ofSEQ ID NO: 21; all or part of a hydrophilic sequence, e.g., the sequencefrom about amino acid 6 to 32, from about 131 to 146, from about 166 to181, and from about 222 to 232 of SEQ ID NO: 21.

[0099] Proteases are enzymes that cleave proteins at single, specificpeptide bonds. Proteases can be classified into four generic classes;serine, thiol or cysteinyl, acid or aspartyl, and metalloproteases(Cuypers et al., J. Biol. Chem. 257:7086 (1982)). Proteases areessential to a variety of biological activities, such as digestion,formation and dissolution of blood clots, reproduction, cell growth, andthe mounting of an immune reaction to foreign cells and organisms.Aberrant proteolysis is associated with a number of disease states inman and other mammals.

[0100] The serine proteases include enzymes such as elastase (humanleukocyte), cathepsin G, plasmin, C-1 esterase, C-3 convertase,urokinase, plasminogen activator, acrosin, and kallikreins. Thetrypsin-like subclass of serine proteases include chymotrypsin, trypsin,thrombin, plasmin, Factor Xa. Certain trypsin-like proteases such asthrombin, plasmin, and Factor Xa, occupy a central role in hemostasisand thrombosis.

[0101] Homeostasis, the control of bleeding, is regulated by thephysiological properties of vasoconstriction and coagulation. Undernormal hemostatic circumstances, the body maintains an acute balancebetween clot formation and clot removal (fibrinolysis). The bloodcoagulation cascade involves the conversion of a variety of inactiveenzymes (zymogens) into active enzymes which ultimately convert thesoluble plasma protein fibrinogen into an insoluble matrix of highlycross-linked fibrin, Davie, E. J. et al., “The Coagulation Cascade:Initiation, Maintenance and Regulation,” Biochemistry, 30, 10363-10370(1991). The coagulation cascade is initiated with the activation ofFactor X by activated Factor VII and Tissue Factor. Factor Xa and FactorVIa are both trypsin-like serine proteases, which are involved inplatelet activation and thrombus formation. In certain diseases of thecardiovascular system, deviations from normal hemostasis push thebalance of clot formation and clot dissolution towards life-threateningthrombus formation when thrombi occlude blood flow in coronary vessels(myocardial infarctions) or limb and pulmonary veins (venousthrombosis).

[0102] Proteases are a major target for drug action and development.Accordingly, it is valuable to the field of pharmaceutical developmentto identify and characterize protease enzymes. The present inventionadvances the state of the art by providing a human serine protease. Theinvention further provides the opportunity to identify inhibitors and/oractivators of a serine proteolytic enzyme, which may be useful intreating thrombosis-related and other serine protease-related disorders.

[0103] The 14081 protein contains a number of structural characteristicsin common with members of the serine protease family. Among thesecharacteristics are domains required for substrate binding, specificity,and catalysis. In particular serine proteases have a critical serineresidue in the active site or catalytic domain of the enzyme that isrequired for catalysis. Typically, the catalytic domain has theconsensus sequence -G-D-S-G-G-P-L- (SEQ ID NO: 24) surrounding theactive Ser residue.

[0104] As used herein, the term “serine protease” includes a protein orpolypeptide that is capable of degrading protein, which has a serineresidue at its catalytic center. A specific class of serine proteases,the trypsin-like serine proteases, share homology with the proteasetrypsin. Some trypsin-like serine proteases (e.g., trypsin,chymotrypsin, and elastase) are digestive enzymes that catalyze thebreakdown of protein in food. Other trypsin-like serine proteases (e.g.,thrombin, plasmin, factor Xa) participate in the regulation of thecoagulation cascade to regulate homeostasis. Trypsin-like and otherserine proteases differ in their protein specificity that is, each isactive only against the peptide bonds in protein molecules that havecarboxyl groups donated by certain amino acids. For the enzyme trypsin,these amino acids are arginine and lysine, for chymotrypsin they aretyrosine, phenylalanine, tryptophan, methionine, and leucine. Trypsin isthe most discriminating of all the proteolytic enzymes in terms of therestricted number of chemical bonds that it will attack. Trypsin cleavesvery specifically at R—X and K—X bonds. If X═P, no cleavage occurs.

[0105] Members of a serine protease family of proteins share a commoncatalytic mechanism characterized structurally by the possession of areactive serine (Ser) residue that is essential for their enzymaticactivity. Conserved histidine (His) (e.g., located anywhere fromresidues 41-46 of SEQ ID NO: 21) and arginine (Arg) residues, which withSer (located anywhere from residues 193-204 of SEQ ID NO: 21) make upwhat is known as the catalytic triad, are also catalytically essential.The His and Ser residues are located at the substrate-binding sitetogether with the conserved Asp, which is commonly buried in a solventinaccessible pocket in a folded serine protease protein. Alignment amongfamily members of the trypsin-like proteases (e.g., trypsin,chyrmotrypsin, bovine trypsin, and pocine elastase) shows that theseenzymes are about 40% identical in their internal sequences, and theirinternal sequences are even more alike (Voet & Voet, Biochemistry, JohnWiley & Sons, New York, N.Y. p. 373-382 (1990)).

[0106] A 14081 polypeptide can include a “serine protease domain” orregions homologous with a “serine protease domain”. A 14081 polypeptidecan further include a “trypsin-like serine protease domain” or regionshomologous with a “trypsin-like serine protease domain.” and at leastone catalytic triad.

[0107] As used herein, the term “trypsin-like domain” includes an aminoacid sequence of about 4 to 242 amino acid residues in length and havinga bit score for the alignment of the sequence to the trypsin-like domain(HMM) of at least 280. Preferably a trypsin-like domain mediatesproteolytic degradation of proteins and polypeptides. Preferably, atrypsin-like domain includes at least about 5 to 10 amino acids, morepreferably about 10 to 100 amino acid residues, more preferably 100 to200, or about 200 to 250 amino acids and has a bit score for thealignment of the sequence to the trypsin-like domain (HMM) of at least50, more preferably 100, most preferably 200 or greater.

[0108] As mentioned above, the trypsin-like domain can include atrypsin-like catalytic domain having a catalytic triad. In the aboveconserved signature sequence, and other motifs or signature sequencesdescribed herein, the standard IUPAC one-letter code for the amino acidsis used. Each element in the pattern is separated by a dash (-); squarebrackets ([]) indicate the particular residues that are accepted at thatposition; x indicates that any residue is accepted at that position; andnumbers in parentheses (( )) indicate the number of residues representedby the accompanying amino acid. The consensus sequence surrounding theactive site of trypsin is -G-D-S-G-G-P-L- (SEQ ID NO: 24) located aboutamino acids 197 to 203 of SEQ ID NO: 21 of human 14081 polypeptide. Thetrypsin-like domain (amino acids 4 to 242 of SEQ ID NO: 21) of human14081 aligns with the trypsin consensus amino acid sequence (SEQ ID NO:23) derived from a hidden Markov model.

[0109] In a preferred embodiment, a 14081 polypeptide or protein has a“trypsin-like domain” or a region which includes at least about 5 to 10more preferably about 100 to 200 or 200 to 250 amino acid residues andhas at least about 60%, 70% 80% 90% 95%, 99%, or 100% homology with a“trypsin-like domain,” e.g., the trypsin-like domain of human 14081(e.g., residues 4 to 242 of SEQ ID NO: 21).

[0110] To identify the presence of a “trypsin-like” domain in a 14081protein sequence, and make the determination that a polypeptide orprotein of interest has a particular profile, the amino acid sequence ofthe protein can be searched against the Pfam database of HMMs (e.g., thePfam database, release 2.1) using the default parameters. For example,the hmmsf program, which is available as part of the HMMER package ofsearch programs, is a family specific default program for MILPAT0063 anda score of 15 is the default threshold score for determining a hit.Alternatively, the threshold score for determining a hit can be lowered(e.g., to 8 bits). A description of the Pfam database can be found inSonhammer et al. (1997) Proteins 28:405-420 and a detailed descriptionof HMMs can be found, for example, in Gribskov et al. (1990) Meth.Enzymol. 183:146-159; Gribskov et al. (1987) Proc. Natl. Acad. Sci. USA84:4355-4358; Krogh et al. (1994) J. Mol. Biol. 235:1501-1531; andStultz et al. (1993) Protein Sci. 2:305-314, the contents of which areincorporated herein by reference. A search was performed against the HMMdatabase resulting in the identification of a “trypsin-like domain”domain in the amino acid sequence of human 14081 at about residues 4 to242 of SEQ ID NO: 21.

[0111] A 14081 polypeptide can include at least one, preferably two“transmembrane domains” or regions homologous with a “transmembranedomain”. As used herein, the term “transmembrane domain” includes anamino acid sequence of about 10 to 40 amino acid residues in length andspans the plasma membrane. Transmembrane domains are rich in hydrophobicresidues, e.g., at least 40%, 50%, 60%, 70%, 80%, 90%, 95% or more ofthe amino acids of a transmembrane domain are hydrophobic, e.g.,leucines, isoleucines, tyrosines, or tryptophans. Transmembranedomains.typically have alpha-helical structures and are described in,for example, Zagotta et al., (1996) Annual Rev. Neurosci. 19:235-263,the contents of which are incorporated herein by reference. Thetransmembrane domains of human 14081 are located at about residues 106to 122 and about residues 203 to 219 of SEQ ID NO: 21.

[0112] To identify the presence of a “transmembrane” domain in a 14081protein sequence, and make the determination that a polypeptide orprotein of interest has a particular profile, the amino acid sequence ofthe protein can be analyzed by a transmembrane prediction method thatpredicts the secondary structure and topology of integral membraneproteins based on the recognition of topological models (MEMSAT, Joneset al., (1994) Biochemistry 33:3038-3049).

[0113] A 14081 polypeptide can include at least one, preferably three“non-transmembrane regions.” As used herein, the term “non-transmembraneregion” includes an amino acid sequence not identified as atransmembrane domain. The non-transmembrane regions in 14081 are locatedat about amino acids 1 to 105, 123 to 202, and 220 to 260 of SEQ ID NO:21. The second non-transmembrane domain (amino acids 123 to 202) ispredicted to be intracellular.

[0114] The non-transmembrane regions of 14081 include at least onecytoplasmic region. In one embodiment, a 14081 cytoplasmic regionincludes at least one, cytoplasmic loop. As used herein, the term “loop”includes an amino acid sequence which is not included within aphospholipid membrane, having a length of at least about 4, preferablyabout 5 to 30, more preferably about 6 to 60, most preferably 6 to 80 ormore amino acid residues, and has an amino acid sequence that connectstwo transmembrane domains within a protein or polypeptide. Accordingly,the N-terminal amino acid of a loop is adjacent to a C-terminal aminoacid of a transmembrane domain in a 14081 molecule, and the C-terminalamino acid of a loop is adjacent to an N-terminal amino acid of atransmembrane domain in a 14081 molecule. As used herein, a “cytoplasmicloop” includes a loop located inside of a cell or within the cytoplasmof a cell. For example, a “cytoplasmic loop” can be found at about aminoacid residues 123 to 202 of SEQ ID NO: 21.

[0115] In a preferred embodiment, a 14081 polypeptide or protein has acytoplasmic loop or a region which includes at least about 4, preferablyabout 5 to 30, and more preferably about 6 to 60, most preferably 6 to80 or more amino acid residues and has at least about 60%, 70% 80% 90%95%, 99%, or 100% homology with a cytoplasmic loop,” e.g., a cytoplasmicloop of human 14081 (e.g., residues 123 to 202 of SEQ ID NO: 21).

[0116] In another embodiment, a 14081 non-transmembrane region includesat least one, two, preferably three non-cytoplasmic loops. As usedherein, a “non-cytoplasmic loop” includes a loop located outside of acell or within an intracellular organelle. Non-cytoplasmic loops includeextracellular domains (i.e., outside of the cell) and intracellulardomains (i.e., within the cell). When referring to membrane-boundproteins found in intracellular organelles (e.g., mitochondria,endoplasmic reticulum, peroxisomes microsomes, vesicles, endosomes, andlysosomes), non-cytoplasmic loops include those domains of the proteinthat reside in the lumen of the organelle or the matrix or theintermembrane space. For example, a “non-cytoplasmic loop” can be foundat about amino acid residues 123 to 202 of SEQ ID NO: 21.

[0117] In a preferred embodiment, a 14081 polypeptide or protein has atleast one non-cytoplasmic loop or a region which includes at least about4, preferably about 5 to 30, more preferably about 6 to 60 mostpreferably 6 to 80 or more amino acid residues and has at least about60%, 70% 80% 90% 95%, 99%, or 100% homology with a “non-cytoplasmicloop,” e.g., at least one non-cytoplasmic loop of human 14081 (e.g.,residues 1 to 105, 123 to 202, and 220 to 260 of SEQ ID NO: 21).

[0118] A human 14081 protein can further include at least one tyrosinekinase phosphorylation site (e.g., at residues 48 to 56 and 167 to 173)or an amidation site (e.g., at residues 189 to 192) or a glycosylationsite (e.g., at residues 25 to 28 and 49 to 52) or a myristoylation site(e.g., at residues 7 to 12, 26 to 31, 32 to 37, and 88 to 93).

[0119] A 14081 family member can include at least one trypsin-likedomains; and optionally a transmembrane or non-transmembrane domain.Furthermore, a 14081 family member can include at least one, preferablytwo protein kinase C phosphorylation sites (Prosite PS00005); at leastone, two, and preferably three casein kinase II phosphorylation sites(Prosite PS00006); at least one, preferably two N-glycosylation sites(Prosite PS00001); and at least one, two, three, and preferably fourN-myristoylation sites (Prosite PS00008).

[0120] As the 14081 polypeptides of the invention can modulate14081-mediated activities, they can be useful for developing noveldiagnostic and therapeutic agents for trypsin-like serineprotease-associated or other 14081-associated disorders, as describedbelow.

[0121] As used herein, a “serine protease-associated activity” includesan activity which involves “trypsin-like serine protease activity,”which degrade proteins with varying specificity. Members of this familycan play a role in diseases involving biological activities such asdigestion formation and dissolution of blood clots, reproduction, cellgrowth, and the immune reaction to foreign cells and organisms. Suchdiseases include cardiovascular and non-cardiovascular diseases such asatherosclerosis, myocardial infarction, unstable angina, stroke,restenosis, deep vein thrombosis, disseminated intravascular coagulationcaused by trauma, reperfusion damage, sepsis or tumor metastasis,hemodialysis, cardiopulmonary bypass surgery, atherectomy, arterialstent placement, adult respiratory distress syndrome, edotoxic shock,rheumatoid arthritis, ulcerative colitis, induration, metastasis,hypercoagulability during chemotherapy, adult respiratory distresssyndrome, Alzheimer's disease, Parkinson's disease, Down's syndrome,inflammation such as edema, pancreatitis, and cancer.

[0122] As used herein, a “14081 activity”, “biological activity of14081” or “functional activity of 14081”, refers to an activity exertedby a 14081 protein, polypeptide or nucleic acid molecule on e.g., a14081-responsive cell or on a 14081 substrate, e.g., a proteinsubstrate, as determined in vivo or in vitro. In one embodiment, a 14081activity is a direct activity, such as an association with a 14081target molecule. A “target molecule” or “binding partner” is a moleculewith which a 14081 protein binds or interacts in nature. In an exemplaryembodiment, 14081 is a receptor (or transporter or protease), e.g., atrypsin-like protease, and thus binds to or interacts in nature with amolecule(or protein substrate), e.g., an organic ion.(or signalpeptide).

[0123] In an exemplary embodiment, 14081 is an enzyme for a protein orpolypeptide substrate.

[0124] A 14081 activity can also be an indirect activity, e.g., acellular signaling activity mediated by interaction of the 14081 proteinwith a 14081 receptor. Based on the above-described sequence structuresand similarities to molecules of known function, the 14081 molecules ofthe present invention can have similar biological activities astrypsin-like serine protease family members. For example, the 14081proteins of the present invention can have one or more of the followingactivities: (1) the ability to degrade proteins; and (2) the ability tophosphorylate carbohydrates. The ability to degrade proteins is based onthe ability to bind, hydrolyze, and release a protein. The catalyticmechanism of serine proteases has been studies extensively. In general,to bind a molecule, the serine protease binds a protein substrate toform a Michaelis complex and the Ser residue nucleophilically attacksthe scisslile peptide's carbonyl group to form a tetrahedralintermediate, wherein the Asp remains a carboxylate ion. The tetrahydralintermediate has a well defined, although transient existence. Duringthe hydrolysis step, the tetrahedral intermediate decomposes to anacyl-enzyme intermediate under the driving force of proton domation fromthe His. The amine leaving group is released from the enzyme and replaceby water from the solvent. The acyl-enzyme intermediate is extremelyunstable to gydrolytic cleavage because of the enzyme's catalyticproperties. Next, a deacylation step proceeds largely through thereversal of the previous steps with the release of the carboylateproduct (the new C-terminal portion of the cleaved polypeptide chain)and the concomitant regeneration of the enzyme.

[0125] The 14081 molecules of the invention can modulate the activitiesof cells in tissues where they are expressed. For example, TaqMan anysisshows that 14081 mRNA is expressed in hemangioma, kidney, pituitary,spinal cord, prostate tumor, human umbilical vein endothelial cells,hypothalamus, normal breast, bone marrow megakaryocytes, isolated CD61+cells, brain cortex, tonsil, and platelets from patients with ischemicheart disease. Accordingly, the 14081 molecules of the invention can actas therapeutic or diagnostic agents for renal, hormonal, endocrine,neurological, hyperprolifereative, reproductive, breast, hematologicaland inflammatory disorders.

[0126] As a preferred embodiment, the 14081 molecules can be used totreat coagulation-related disorders in part because the 14081 mRNA isexpressed in the platelets of patients with ischemic heart disease. Inaddition, 14081 levels are increased in samples from patients withcoronary artery disease. Thus, the 14081 molecules can act as noveldiagnostic targets and therapeutic agents for controlling one or morecoagulation or other serine protease or trypsin-like serine proteasedisorders. As used herein, “serine protease disorders” or “trypsin-likeserine protease disorders” are diseases or disorders whose pathogenesisis caused by, is related to, or is associated with aberrant or deficientserine protease or trypsin-like serine protease protein function orexpression. Examples of such disorders, e.g., trypsin-like serineprotease-associated or other 14081-associated disorders, include but arenot limited to, cellular proliferative and/or differentiative disorders,disorders associated with metabolism (e.g., hormonal), immune e.g.,inflammatory, disorders. cardiovascular disorders, endothelial celldisorders, renal disorders, neurological disorders, hyperprolifereativedisorders, reproductive disorders, breast disorders, and hematologicaldisorders.

[0127] The 14081 molecules can be used to treat cellular proliferativeand/or differentiative disorders in part because trypsin-like serineprotease family members are found in the prostate tumors. Examples ofcellular proliferative and/or differentiative disorders include cancer,e.g., carcinoma, sarcoma, metastatic disorders or hematopoieticneoplastic disorders, e.g., leukemias. A metastatic tumor can arise froma multitude of primary tumor types, including but not limited to thoseof prostate, colon, lung, breast and liver origin.

[0128] The 14081 molecules can be used to treat immune disorders in partbecause trypsin-like serine protease family members are found in thebone marrow megakaryocytes, CD61+ cells, and platelets. Moreparticularly, the 14081 nucleic acid and protein of the invention can beused to treat and/or diagnose a variety of immune, e.g., inflammatory,(e.g. respiratory inflammatory) disorders, as described herein.

[0129] The 14081 molecules can be used to treat cardiovascular disordersin part because trypsin-like serine protease family members are found inthe platelets and participate in platelet activation and thrombusformation. In addition, 14081 levels are increased in samples frompatients with coronary artery disease. 14081 may cleave andactivate-channels regulating platelet function. Antagonizing 14081 willblock platelet activation.

[0130] The 14081 molecules can be used to treat endothelial celldisorders in part because trypsin-like serine protease family membersare found in the human umbilical endothelial cells.

[0131] The 14081 molecules can be used to treat metabolic disorders inpart because trypsin-like serine protease family members are found inthe pituitary gland. 14081 can play an important role in the regulationof metabolism or pain disorders.

[0132] Human 32140

[0133] The present invention is based, in part, on the discovery of anovel human aldehyde dehydrogenase, referred to herein as “32140”.

[0134] The human 32140 sequence (SEQ ID NO: 25), which is approximately7220 nucleotides long including untranslated regions, contains apredicted methionine-initiated coding sequence of about 2769 nucleotides(nucleotides 129-2897 of SEQ ID NO: 25; nucleotides 1-2769 of SEQ ID NO:27), not including the terminal codon. The coding sequence encodes a 923amino acid protein (SEQ ID NO: 26).

[0135] Human 32140 contains the following regions: a predicted aldehydedehydrogenase domain (PFAM Accession PF00171) located at about aminoacid residues 450-923 of SEQ ID NO: 26, and a predicted formyltransferase (PFAM Accession PF00551) located at about amino acidresidues 23-202 of SEQ ID NO: 26.

[0136] The 32140 protein also includes the following domains: a“10-formyltetrahydrofolate dehydrogenase domain” at about amino acidresidues 265-336 of SEQ ID NO: 26, and a“formyltransferase/methyltransferase domain” at about amino acidresidues 211-328 of SEQ ID NO: 26.

[0137] For general information regarding PFAM identifiers, PS prefix andPF prefix domain identification numbers, refer to Sonnhammer et al.(1997) Protein 28:405-420.

[0138] A plasmid containing the nucleotide sequence encoding human 32140was deposited with American Type Culture Collection (ATCC), 10801University Boulevard, Manassas, Va. 20110-2209, on Jun. 1, 2001 andassigned Accession Number PTA-3424. This deposit will be maintainedunder the terms of the Budapest Treaty on the International Recognitionof the Deposit of Microorganisms for the Purposes of Patent Procedure.This deposit was made merely as a convenience for those of skill in theart and is not an admission that a deposit is required under 35 U.S.C.§112.

[0139] The 32140 protein contains a significant number of structuralcharacteristics in common with members of the aldehyde dehydrogenasefamily. As used herein, the term “aldehyde dehydrogenase” refers to aprotein or polypeptide which is capable of catalyzing an aldehydeoxidation reaction. Aldehyde dehydrogenases can have a specificity forvarious aldehyde precursors. An aldehyde dehydrogenase polypeptidetypically includes a region of sequence similarity that comprises boththe NAD⁺/NADP binding site and the enzyme active site (Vasiliou et al.,(1999) Pharmacogenetics 9:421-434). This region of sequence similarityis located at about amino acids 669-728 of SEQ ID NO: 26. The 32140polypeptide exhibits sequence identity with the aldehyde dehydrogenasefamily at four key amino acid residues that have been shown to beimportant for aldehyde dehydrogenase function, including a glutamateinvolved in catalytic activity (amino acid 694 of SEQ ID NO: 26), acysteine involved in substrate binding (amino acid 728 of SEQ ID NO:26), and two glycines involved in NAD⁺ or NADP binding (amino acids 671and 676 of SEQ ID NO: 26).

[0140] Typically, aldehyde dehydrogenases play a role in a wide varietyof cellular processes. For example, the metabolism of many amino acids,fatty acids, and glycerolipids, as well as ascorbate, aldarate,butanoate, pyruvate, propanoate, and 4-aminobutyric acid (GABA),involves specific oxidation reactions catalyzed by aldehydedehydrogenases. Aldehyde dehydrogenases also participate in retinoidsignaling, catalyzing the oxidation of retinal (which is required forvision) to retinoic acid (which plays an important role as a signalingmolecule in embryonic differentiation) (reviewed by Duester, inEnzymology and Molecular Biology of Carbonyl Metabolism, KeuwerAcademic/Plenum Publishers,1989). Thus, the molecules of the presentinvention may be involved in one or more of: 1) the oxidation of analdehyde; 2) the modulation of amino acid metabolism; 3) the modulationof fatty acid or glycerophospholipid metabolism; 4) the modulation ofretinoic acid signaling; 5) the modulation of cell differentiation; 6)the modulation of vision; 7) the modulation of 4-aminobutyric acid(GABA) metabolism; 8) the modulation of the metabolism of drugs orenvironmental agents; 9) the modulation of alcohol metabolism;10) themodulation of tumor cell growth and invasion; or 11) the modulation ofvitamin metabolism.

[0141] A 32140 polypeptide can include an “aldehyde dehydrogenasedomain” or regions homologous with an “aldehyde dehydrogenase domain”.As used herein, the term “aldehyde dehydrogenase domain” includes anamino acid sequence of about 80-300 amino acid residues in length andhaving a bit score for the alignment of the sequence to the aldehydedehydrogenase domain (HMM) of at least 8. Preferably, an aldehydedehydrogenase domain includes at least about 100-250 amino acids, morepreferably about 130-200 amino acid residues, or about 160-200 aminoacids and has a bit score for the alignment of the sequence to thealdehyde dehydrogenase domain (HMM) of at least 16 or greater. Thealdehyde dehydrogenase domain (HMM) has been assigned the PFAM AccessionPF00171. The aldehyde dehydrogenase domain (amino acids 450-923 of SEQID NO: 26) of human 32140 aligns with a consensus amino acid sequencederived from a hidden Markov model (SEQ ID NO: 28).

[0142] In a preferred embodiment, 32140 polypeptide or protein has a“aldehyde dehydrogenase domain” or a region which includes at leastabout 100-250 more preferably about 130-200 or 160-200 amino acidresidues and has at least about 60%, 70%, 80%, 90%, 95%, 99%, or 100%homology with an “aldehyde dehydrogenase domain,” e.g., the aldehydedehydrogenase domain of human 32140 (e.g., amino acid residues 450-923of SEQ ID NO: 26).

[0143] To identify the presence of an “aldehyde dehydrogenase” domain ina 32140 protein sequence, and make the determination that a polypeptideor protein of interest has a particular profile, the amino acid sequenceof the protein can be searched against a database of HMMs (e.g., thePfam database, release 2.1) using the default parameters. For example,the hmmsf program, which is available as part of the HMMER package ofsearch programs, is a family specific default program for MILPAT0063 anda score of 15 is the default threshold score for determining a hit.Alternatively, the threshold score for determining a hit can be lowered(e.g., to 8 bits). A description of the Pfam database can be found inSonhammer et al., (1997) Proteins 28(3):405-420 and a detaileddescription of HMMs can be found, for example, in Gribskov et al.,(1990) Meth. Enzymol. 183:146-159; Gribskov et al., (1987) Proc. Natl.Acad. Sci. USA 84:4355-4358; Krogh et al., (1994) J. Mol. Biol.235:1501-1531; and Stultz et al., (1993) Protein Sci. 2:305-314, thecontents of which are incorporated herein by reference.

[0144] As the 32140 polypeptides of the invention may modulate32140-mediated activities, they may be useful for developing noveldiagnostic and therapeutic agents for 32140-mediated or relateddisorders, as described below.

[0145] As used herein, a “32140 activity”, “biological activity of32140” or “functional activity of 32140”, refers to an activity exertedby a 32140 protein, polypeptide or nucleic acid molecule on e.g., a32140-responsive cell or on a 32140 substrate, e.g., a lipid or proteinsubstrate, as determined in vivo or in vitro. In one embodiment, a 32140activity is a direct activity, such as an association with a 32140target molecule. A “target molecule” or “binding partner” is a moleculewith which a 32140 protein binds or interacts in nature, e.g., analdehyde, which the 32140 protein oxidizes. A 32140 activity can also bean indirect activity, e.g., a cellular signaling activity mediated byinteraction of the 32140 protein with a 32140 ligand. For example, the32140 proteins of the present invention can have one or more of thefollowing activities: 1) the oxidation of an aldehyde; 2) the modulationof amino acid metabolism; 3) the modulation of fatty acid orglycerophospholipid metabolism; 4) the modulation of retionic acidsignaling; 5) the modulation of cell differentiation; 6) the modulationof vision; 7) the modulation of 4-aminobutyric acid (GABA) metabolism;8) the modulation of the metabolism of drugs or environmental agents; 9)the modulation of alcohol metabolism;10) the modulation of tumor cellgrowth and invasion; or 11) the modulation of vitamin metabolism. 12)the ability to antagonize or inhibit, competitively ornon-competitively, any of 1-11.

[0146] Accordingly, 32140 protein may mediate various disorders,including cellular proliferative and/or differentiative disorders, lungdisorders, liver disorders, brain disorders, heart disorders, kidneydisorders, breast disorders, and testis disorders.

[0147] The 32140 nucleic acid and protein of the invention can be usedto treat and/or diagnose a variety of proliferative disorders.

[0148] The 32140 gene appears to have an important role in viralpathogenesis. In particular, Herpes Simples Virus (HSV) inducesexpression of the novel 10-formyltetrahydrofolate DH encoded by the gene32140, particularly in infected neurons. Viral panels have shown that32140 is induced in HSV-infected mouse ganglia both during active andlatent phases. It is induced up to 5-fold in HSV-infected neuroblastoma(Ntera2). 32140 appears to be a 10-formyltetrahydrofolate DH isozymewhich is expressed in different tissues (e.g. neuronal tissues) comparedto the known 10-formyltetrahydrofolate DH. The 32140 aldehydedehydrogenase is therfore an important host gene for HSV infection andfinds use in the treatment of disorders resulting from Herpes SimplesVirus (HSV) and hepatitis B infection. Also, gene 32140 is inducedduring infection by HSV, but not infection with other viruses such asVZV, HBV,and HCV.

[0149] Gene Expression Analysis of 32140

[0150] TaqMan analysis shows 32140 was expressed in different cells:normal or uninfected liver; uninfected ganglia and ganglia infected withHerpes Simplex Virus; a time course of HSV (strain 17+) infection ofhuman Ntera2 neuroblastoma cells (times are 0, 2.5, 5, and 7 hourspost-infection); same infection experiment using HSV strain KOS; a timecourse of Varicella Zoster virus (VZV) infected human MRC5 (lungfibroblast cells) (times are 0, 18 and 72 hours post-infection); andNtera2 cells infected with an adenovirus that expresses the HSV ICPOtranscription factor.

[0151] TaqMan analysis also shows 32140 was expressed in differenttissues: “normal” liver, lung and kidney tissue; uninfected ganglia andganglia infected with Herpes Simplex Virus; HSV (strain 17+) infectionof human Ntera2 neuroblastoma cells (times are 0, 2.5, 5, and 7 hourspost-infection); a time course of Varicella Zoster virus (VZV) infectedhuman MRC5 (lung fibroblast cells) (times are 0, 18 and 72 hourspost-infection); Ntera2 cells infected with an adenovirus that expressesthe HSV ICPO transcription factor; hepatitis B virus (HBV) expressingHepG2.2.15 cells compared to the parental HepG2 cell control; andHBV-infected and hepatitis C virus (HCV)- infected liver samples.

[0152] Gene 32140 is highly expressed in salivary glands and testes,more moderately expressed in brain, small intestine, stomach, spinalcord, and dorsal root ganglia, and it is expressed at lower levels inthe other tissues indicated.

[0153] Human 50352

[0154] The present invention is based, in part, on the discovery of anovel ubiquitin-protein ligase family member, referred to herein as“50352”.

[0155] The human 50352 sequence (SEQ ID NO: 29), which is approximately3513 nucleotides long including untranslated regions, contains apredicted methionine-initiated coding sequence of about 3066nucleotides, not including the termination codon (nucleotides 82-3147 ofSEQ ID NO: 29; 1-3066 of SEQ ID NO: 31). The coding sequence encodes a1022 amino acid protein (SEQ ID NO: 30).

[0156] Human 50352 contains the following regions or other structuralfeatures (for general information regarding PFAM identifiers, PS prefixand PF prefix domain identification numbers, refer to Sonnhammer et al.(1997) Protein 28:405-420:

[0157] One, two, three, preferably four and most preferably five or moreregulator of chromosome condensation domain(s) (PFAM Accession NumberPF00415; SEQ ID NO: 32) located at about amino acid residues 43 to 92,from about residues 93 to 145, from about residues 146 to 198, fromabout residues 200 to 253 and from about residues 254 to 304 of SEQ IDNO: 30; a homologous to the E6-AP carboxyl terminus domain (PFAMAccession Number PF00632; SEQ ID NO: 33) located at about amino acidresidues 726 to 1015 of SEQ ID NO: 30; a conjugation ubiquitin cyclinKIAA0032 binding CG9153 cyclin E domain (ProDom Accession NumberPD136613) located at about amino acids 374 to 645 of SEQ ID NO: 30; aligase ubiquitin conjugation ubiquitin-protein 6.3.2 domain (ProDomAccession Number PD255820) located at about amino acids 758 to 811 ofSEQ ID NO: 30; a ligase ubiquitin conjugation 6.3.2 domain (ProDomAccession Number PD002225) located at about amino acids 836 to 1013 ofSEQ ID NO: 30; fourteen protein kinase C phosphorylation sites (PrositePS00005) located at about amino acids 118 to 120, 216 to 218, 224 to226, 319 to 321, 368 to 370, 443 to 445, 448 to 450, 647 to 649, 669 to671, 801 to 803, 850 to 852, 867 to 869, 951 to 953, and 975 to 977 ofSEQ ID NO: 30; twenty five casein kinase II phosphorylation sites(Prosite PS00006) located at about amino acids 46 to 49, 124 to 127, 242to 245, 259 to 262, 290 to 293, 323 to 326, 339 to 342, 362 to 365, 375to 378, 385 to 388, 398 to 401, 431 to 434, 448 to 451, 459 to 462, 550to 553, 690 to 693, 729 to 732, 793 to 796, 807 to 810, 904 to 907, 915to 918, 939 to 942, 951 to 954, 973 to 976, and 995 to 998 of SEQ ID NO:30; four cAMP/cGMP-dependent protein kinase phosphorylation sites(Prosite PS00004) located at about amino acids 14 to 17, 394 to 397, 424to 427, and 445 to 448 of SEQ ID NO: 30; two N-glycosylation sites(Prosite PS00001) located at about amino acids 263 to 266 and 865 to 868of SEQ ID NO: 30; thirteen N-myristoylation sites (Prosite PS00008)located at about amino acids 19 to 24, 59 to 64, 180 to 185, 189 to 194,200 to 205, 206 to 211, 231 to 236, 295 to 300, 307 to 312, 354 to 359,426 to 431, 714 to 719, and 762 to 767 of SEQ ID NO: 30; one tyrosinekinase phosphorylation site (Prosite PS00007) located at about aminoacids 750 to 758 of SEQ ID NO: 30; one amidation site (Prosite PS00009)located at about amino acids 55 to 58 of SEQ ID NO: 30; and one, two,three, preferably four and most preferably five regulator of chromosomecondensation signature 2 domain(s) (Prosite PS00626) located at aboutamino acids 28 to 38, 80 to 90, 133 to 143, 186 to 196, and 241 to 251of SEQ ID NO: 30.

[0158] A hydropathy plot of human 50352 was performed. Polypeptides ofthe invention include fragments which include: all or part of ahydrophobic sequence, e.g., the sequence from about amino acid 71 to 81,from about 411 to 421, from about 475 to 490, from about 500 to 510,from about 532 to 544, from about 615 to 631, from about 695 to 705, andfrom about 761 to 772 of SEQ ID NO: 30; all or part of a hydrophilicsequence, e.g., the sequence from about amino acid 5 to 20, from about48 to 63, from about 261 to 280, from about 312 to 325, from about 392to 403, from about 439 to 451, from about 551 to 560, from about 660 to670, from about 749 to 757, from about 851 to 861, and from about 903 to928 of SEQ ID NO: 30; a sequence which includes a Cys, or aglycosylation site.

[0159] The 50352 protein contains a significant number of structuralcharacteristics in common with members of the ubiquitin-protein ligasefamily.

[0160] As used herein, the term “ubiquitin-protein ligase” includes aprotein or polypeptide which is capable of conjugating ubiquitinmolecules to either substrates or to ubiquitin moieties bound tosubstrates deemed for degradation. Ubiquitin-protein ligases areresponsible for the third and final step of ubiquitin conjugation, theyaccept ubiquitin from an E2 ubiquitin-conjugated enzyme in the form of athioester and then transfer the ubiquitin to a target protein by formingan isopeptide bond between glycine residues of ubiquitin and an alphaamino group of a lysine residue of the substrate or of a previouslyconjugated ubiquitin. Ubiquitin-protein ligases are also responsible indetermining the specificity of ubiquitination. Members of theubiquitin-protein ligase family of proteins share a region of similarityknown as the homologous to the E6-AP carboxyl terminus domain. Thisdomain is composed of approximately 350 amino acids and it has aconserved cysteine residue located in the last 32 to 46 amino acidswhich is necessary for the ubiquitin thioester formation.

[0161] In one embodiment of the invention, a 50352 polypeptide includesat least one, two, three, preferably four and most preferably five ormore regulator of chromosome condensation domain.

[0162] In another embodiment of the invention, a 50352 polypeptideincludes at least one “homologous to the E6-AP carboxyl terminus”domain.

[0163] A 50352 polypeptide can include a “homologous to the E6-APcarboxyl terminus domain” or regions homologous with a “homologous tothe E6-AP carboxyl terminus domain”. A 50352 polypeptide can furtherinclude one, two, three, preferably four, and most preferably five ormore “regulator of chromosome condensation domain(s)” or regionshomologous with a “regulator of chromosome condensation domain”.

[0164] As used herein, the term “homologous to the E6-AP carboxylterminus domain” includes an amino acid sequence of about 250 to 350amino acid residues in length and having a bit score for the alignmentof the sequence to the homologous to the E6-AP carboxyl terminus domain(HMM) of at least 110.9. Preferably a homologous to the E6-AP carboxylterminus domain mediates ubiquitin conjugation and specificity ofubiquitin conjugation to substrates or ubiquitin moieties bound tosubstrates. Preferably, a homologous to the E6-AP carboxyl terminusdomain includes at least about 200 to 400 amino acids, more preferablyabout 225 to 375 amino acid residues, or about 250 to 350 amino acidsand has a bit score for the alignment of the sequence to the homologousto the E6-AP carboxyl terminus domain (HMM) of at least 80, 90, 100, 110or greater.

[0165] In a preferred embodiment, a 50352 polypeptide or protein has a“homologous to the E6-AP carboxyl terminus domain” or a region whichincludes at least about 200 to 400 more preferably about 225 to 375 or250 to 350 amino acid residuesland has at least about 60%, 70% 80% 90%95%, 99%, or 100% homology with a “homologous to the E6-AP carboxylterminus domain,” eg., the homologous to the E6-AP carboxyl terminusdomain of human 50352 (e.g., residues 726 to 1015 of SEQ ID NO: 30).

[0166] To identify the presence of a “homologous to the E6-AP carboxylterminus domain” in a 50352 protein sequence, and make the determinationthat a polypeptide or protein of interest has a particular profile, theamino acid sequence of the protein can be searched against the Pfamdatabase of HMMs (e.g., the Pfam database, release 2.1) using thedefault parameters. For example, the hmmsf program, which is availableas part of the HMMER package of search programs, is a family specificdefault program for MILPAT0063 and a score of 15 is the defaultthreshold score for determining a hit. Alternatively, the thresholdscore for determining a hit can be lowered (e.g., to 8 bits). Adescription of the Pfam database can be found in Sonhammer et al. (1997)Proteins 28:405-420 and a detailed description of HMMs can be found, forexample, in Gribskov et al. (1990) Meth. Enzymol. 183:146-159; Gribskovet al. (1987) Proc. Natl. Acad. Sci. USA 84:4355-4358; Krogh et al.(1994) J. Mol. Biol. 235:1501-1531; and Stultz et al. (1993) ProteinSci. 2:305-314, the contents of which are incorporated herein byreference. A search was performed against the HMM database resulting inthe identification of a “homologous to the E6-AP carboxyl terminusdomain” in the amino acid sequence of human 50352 at about residues 726to 1015 of SEQ ID NO: 30.

[0167] A 50352 molecule can further include one, two, three, preferablyfour, and most preferably five or more “regulator of chromosomecondensation domain(s)”. As used herein, the term “regulator ofchromosome condensation domain” includes amino acid sequence(s) of about40 to 60 amino acid residues in length and having a bit score for thealignment of the sequence to the regulator of chromosome condensationdomain (HMM) of at least 30. Preferably, regulator of chromosomecondensation domain(s) include at least about 20 to 80 amino acids, morepreferably about 30 to 70 amino acid residues, or about 40 to 60 aminoacids and have a bit scores for the alignment of the sequences to theregulator of chromosome condensation domain(s) (HMM) of at least 5, 10,20, 30 or greater.

[0168] Regulator of chromosome condensation domains typically contain aconserved regulator of chromosome condensation signature 2 (RCC_(—)2)pattern which participates in the catalytic mechanism. The conservedRCC_(—)2 pattern is as follows:[LIVMFA]-[STAGC](2)-G-X(2)-H-[STAGLI]-[LIVMFA]-X-[LIVM] (SEQ ID NO: 34).

[0169] In the above conserved signature sequence, and other motifs orsignature sequences described herein, the standard IUPAC one-letter codefor the amino acids is used. Each element in the pattern is separated bya dash (-); square brackets ([]) indicate the particular residues thatare accepted at that position; x indicates that any residue is acceptedat that position; and numbers in parentheses (( )) indicate the numberof residues represented by the accompanying amino acid.

[0170] A 50352 protein contains one, two, three, preferably four, andmost preferably five or greater RCC_(—)2 pattern(s) at about amino acidresidues 28 to 38, 80 to 90, 133 to 143, 186 to 196, and 241 to 251 ofSEQ ID NO: 30.

[0171] In a preferred embodiment, a 50352 polypeptide or protein hasone, two, three, preferably four, and most preferably five or greater“regulator of chromosome condensation domain(s)” or one, two, three,preferably four and most preferably five or more region(s) whichincludes at least about 20 to 80 more preferably about 30 to 40 or 40 to60 amino acid residues and has at least about 60%, 70% 80% 90% 95%, 99%,or 100% homology with a “regulator of chromosome condensation domain,”e.g., the regulator of chromosome condensation domain of human 50352(e.g., residues 43 to 92, 93 to 145, 146 to 198, 200 to 253, and 254 to304 of SEQ ID NO: 30).

[0172] To identify the presence of a “regulator of chromosomecondensation domain” in a 50352 protein sequence, and make thedetermination that a polypeptide or protein of interest has a particularprofile, the amino acid sequence of the protein can be searched againstthe Pfam database of HMMs (e.g., the Pfam database, release 2.1) usingthe default parameters. For example, the hmmsf program, which isavailable as part of the HMMER package of search programs, is a familyspecific default program for MILPAT0063 and a score of 15 is the defaultthreshold score for determining a hit. Alternatively, the thresholdscore for determining a hit can be lowered (e.g., to 8 bits). Adescription of the Pfam database can be found in Sonhammer et al. (1997)Proteins 28:405-420 and a detailed description of HMMs can be found, forexample, in Gribskov et al. (1990) Meth. Enzymol. 183:146-159; Gribskovet al. (1987) Proc. Natl. Acad. Sci. USA 84:4355-4358; Krogh et al.(1994) J. Mol. Biol. 235:1501-1531; and Stultz et al. (1993) ProteinSci. 2:305-314, the contents of which are incorporated herein byreference. A search was performed against the HMM database resulting inthe identification of five “regulator of chromosome condensationdomains” in the amino acid sequence of human 50352 at about residues 43to 92, 93 to 145, 146 to 198, 200 to 253, and 254 to 304 of SEQ ID NO:30.

[0173] For further identification of domains, and make the determinationthat a polypeptide or protein of interest has a particular profile, theamino acid sequence of the protein can be searched against a database ofdomains, e.g., the ProDom database (Corpet et al. (1999), Nucl. AcidsRes. 27:263-267). The ProDom protein domain database consists of anautomatic compilation of homologous domains. Current versions of ProDomare built using recursive PSI-BLAST searches (Altschul et al. (1997)Nucleic Acids Res. 25:3389-3402; Gouzy et al. (1999) Computers andChemistry 23:333-340) of the SWISS-PROT 38 and TREMBL protein databases.The database automatically generates a consensus sequence for eachdomain. A BLAST search was performed against the HMM database resultingin the identification of a “conjugation ubiquitin cyclin KIAA0032binding CG9153 cyclin E” domain in the amino acid sequence of human50352 at about residues 374 to 645 of SEQ ID NO: 30, and two “ligaseubiquitin conjugation ubiquitin-protein 6.3.2” domains in the amino acidsequence of human 50352 at about residues 758 to 811 and 836 to 1013 ofSEQ ID NO: 30.

[0174] A 50352 family member can include at least one homologous to theE6-AP carboxyl terminus domain and at least one, two, three, preferablyfour, and most preferably five or greater regulator of chromosomecondensation domain(s). Furthermore, a 50352 family member can includeat least one, two, three, four, five, six, seven, eight, nine, ten,eleven, twelve, thirteen, and preferably fourteen protein kinase Cphosphorylation sites (Prosite PS00005); at least one, two, three, four,five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen,fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty one,twenty two, twenty three, twenty four, and preferably twenty five caseinkinase II phosphorylation sites (Prosite PS00006); at least one,preferably two N-glycosylation sites (Prosite PS00001); at least one,two, three, and preferably four cAMP/cGMP protein kinase phosphorylationsites (Prosite PS00004); at least one tyrosine kinase phosphorylationsite (Prosite PS00007); at least one amidation site (Prosite PS00009);at least one, two, three, four, five, six, seven, eight, nine, ten,eleven, twelve, and preferably thirteen N-myristoylation sites (PrositePS00008); at least one conjugation ubiquitin cyclin KIAA0032 bindingCG9153 cyclin E domain (ProDom Accession Number PD136613); at least oneligase ubiquitin conjugation ubiquitin-protein 6.3.2 domain (ProDomAccession Number PD255820); and at least one ligase ubiquitinconjugation 6.3.2 domain (ProDom Accession Number PD002225).

[0175] As the 50352 polypeptides of the invention can modulate50352-mediated activities, they can be useful for developing noveldiagnostic and therapeutic agents for ubiquitin-proteinligase-associated or other 50352-associated disorders, as describedbelow.

[0176] Ubiquitin mediated intracellular proteolysis is essential forcell viability. Abnormalities within the ubiquitin pathway, either withubiquitin-protein ligases or with de-ubiquitinating enzymes, causeproblems with substrate recognition or supply of free ubiquitin,respectively. Such abnormalities can lead to or contribute to diseasepathogenesis, such as human neurodegenerative diseases. Layfield et al.,(2001) Neuropathol Appl Neurobiol 27(3):171-179.

[0177] As used herein, a “ubiquitin-protein ligase-mediated activity”includes an activity which involves the addition of ubiquitin to eithersubstrates or ubiquitin moieties bound to substrates. This activityinvolves both the recognition of substrate specificity as well as thecreation of an isopeptide bond between glycine residues of ubiquitin andan alpha amino group of a lysine residue of the substrate or of apreviously conjugated ubiquitin. Therefore, these enzymes areresponsible for recognizing proteins which need to undergo intracellularproteolysis as well as for the attachment of ubiquitin molecules to suchproteins deemed for degradation.

[0178] As used herein, a “50352 activity”, “biological activity of50352” or “functional activity of 50352”, refers to an activity exertedby a 50352 protein, polypeptide or nucleic acid molecule on e.g., a50352-responsive cell or on a 50352 substrate, e.g., a proteinsubstrate, as determined in vivo or in vitro. In one embodiment, a 50352activity is a direct activity, such as an association with a 50352target molecule. A “target molecule” or “binding partner” is a moleculewith which a 50352 protein binds or interacts in nature. A 50352activity can also be an indirect activity, e.g., a cellular signalingactivity mediated by interaction of the 50352 protein with a 50352receptor.

[0179] Based on the above-described sequence structures and similaritiesto molecules of known function, the 50352 molecules of the presentinvention can have similar biological activities as ubiquitin-proteinligase family members. For example, the 50352 proteins of the presentinvention can have one or more of the following activities: (1) theability to modulate ubiquitination of a substrate, e.g., a proteintargeted for degradation; (2) the ability to modulate substratespecificity for ubiquitination; (3) the ability to modulate cellularproliferation and/or differentiation; (4) the ability to modulateapoptosis; (5) the ability to modulate transcription and/or cell-cycleprogression; (6) the ability to modulate signal-transduction; (7) theability to modulate antigen processing; (8) the ability to modulatecell-cell adhesion; (9) the ability to modulate receptor-mediatedendocytosis; (10) the ability to modulate organelle biogenesis anddevelopment; (11) the ability to modulate neuropathological conditions;(12) the ability to modulate oncogenesis, and (13) the ability tomodulate protein levels, e.g., cellular protein levels.

[0180] The 50352 molecules of the invention can modulate the activitiesof cells in tissues where they are expressed. For example, 50352 mRNA isexpressed in human umbilical vain endothelial cells, in human normalbrain cortex, in human colon tumors and in human lung tumors.Accordingly, the 50352 molecules of the invention can act as therapeuticor diagnostic agents for cardiovascular, colon, lung and neurologicaldisorders.

[0181] Thus, the 50352 molecules can act as novel diagnostic targets andtherapeutic agents for controlling one or more ubiquitin-proteinligase-associated or other 50352-associated disorders. As used herein,“ubiquitin-protein ligase disorders” are diseases or disorders whosepathogenesis is caused by, is related to, or is associated with aberrantor deficient ubiquitin-protein ligase function or expression. The 50352molecules can be used to treat neurological disorders in part becausethe 50352 mRNA is expressed in the brain.

[0182] The 50352 molecules can also be used to treat cardiovasculardisorders in part because the 50352 mRNA is expressed in human umbilicalvein endothelial cells.

[0183] The 50352 molecules can also be used to treat colon disorders inpart because the 50352 mRNA is expressed in human colon tumors.

[0184] The 50352 molecules can also be used to treat lung disorders inpart because the 50352 mRNA is expressed in human lung tumors.

[0185] The 50352 molecules and modulators thereof can act as noveltherapeutic agents for controlling one or more of cellular proliferativeand/or differentiative disorders, hormonal disorders, immune andinflammatory disorders, neurological disorders, blood vessel disorders,platelet disorders, cardiovascular disorders, endothelial celldisorders, liver disorders, viral diseases, pain or metabolic disorders.

[0186] Isolation of 50352

[0187] Total RNA was prepared from various human tissues by a singlestep extraction method using RNA STAT-60 according to the manufacturer'sinstructions (TelTest, Inc). Each RNA preparation was treated with DNaseI (Ambion) at 37° C. for 1 hour. DNAse I treatment was determined to becomplete if the sample required at least 38 PCR amplification cycles toreach a threshold level of fluorescence using β-2 microglobulin as aninternal amplicon reference. The integrity of the RNA samples followingDNase I treatment was confirmed by agarose gel electrophoresis andethidium bromide staining. After phenol extraction cDNA was preparedfrom the sample using the SUPERSCRIPT™ Choice System following themanufacturer's instructions (GibcoBRL). A negative control of RNAwithout reverse transcriptase was mock reverse transcribed for each RNAsample.

[0188] Gene Expression of 50352

[0189] TaqMan analysis results indicate significant 50352 expression inhuman umbilical vein endothelial cells, in normal human brain cortex, inlung tumors and in colon tumors.

[0190] Human 16658

[0191] The present invention is based, in part, on the discovery of anovel human kinase, referred to herein as “16658”.

[0192] The human 16658 sequence (SEQ ID NO: 35), which is approximately3633 nucleotides long including untranslated regions, contains apredicted methionine-initiated coding sequence of about 3390 nucleotides(nucleotides 23-3412 of SEQ ID NO: 35; 1-3390 of SEQ ID NO: 37), notincluding the terminal codon. The coding sequence encodes a 1130 aminoacid protein (SEQ ID NO: 36).

[0193] This mature protein form is approximately 1130 amino acidresidues in length (from about amino acid 1 to amino acid 1130 of SEQ IDNO: 36). Human 16658 contains the following regions or other structuralfeatures: a predicted kinase domain located at about amino acid residues725-1021 of SEQ ID NO: 36; and predicted transmembrane domains whichextend from about amino acids 103-119 and 642-665 of SEQ ID NO: 36. Ahydropathy plot of human 16658 was performed. Polypeptides of theinvention include fragments which include: all or part of a hydrophobicsequence, e.g., the sequence from about amino acid 100 to 120, fromabout 280 to 290, and from about 985 to 650 of SEQ ID NO: 36; all orpart of a hydrophilic sequence, the sequence from about amino acid 50 to80, from about 620 to 640, and from about 680 to 690 of SEQ ID NO: 36; asequence which includes a Cys, or a glycosylation site.

[0194] The mature human 16658 protein contains the following structuralfeatures: two predicted transmembrane domains located at about aminoacids 103-119 and 642-665 of SEQ ID. NO: 36. Predicted transmembranedomains extend from about amino acid 103 (cytoplasmic end) to aboutamino acid 119 (extracellular end) of SEQ ID NO: 36; and from aboutamino acid 642 (extracellular end) to about amino acid 665 (cytoplasmicend); one extracellular loop found at about amino acid 120-641 of SEQ IDNO: 36; one N-terminal cytoplasmic domain is found at about amino acidresidues 1-102 of SEQ ID NO: 36; and a C-terminal cytoplasmic domain isfound at about amino acid residues 666-1130 of SEQ ID NO: 36.

[0195] The 16658 protein also includes the following domains: fourN-glycosylation sites (PS00001) located at about amino acids 437-440,491-494, 504-507, and 850-853 of SEQ ID NO: 36; one cAMP- andcGMP-dependent protein kinase phosphorylation site (PS00004) located atabout amino acids 945-948 of SEQ ID NO: 36; sixteen predicted proteinkinase C phosphorylation sites (PS00005) located at about amino acids40-42, 83-85, 201-203, 214-216, 293-295, 304-306, 339-341, 521-523,586-588, 621-623, 666-668, 741-743, 758-760, 794-796, 1066-1068, and1115-1117 of SEQ ID NO: 36; twenty-seven predicted casein kinase IIphosphorylation sites (PS00006) located at about amino 19-22, 83-86,155-158, 201-204, 214-217, 240-243, 252-255, 322-325, 333-336, 361-364,396-399, 471-474, 532-535, 628-631, 699-702, 705-708, 937-940, 949-952,965-968, 975-978, 982-985, 1022-1025, 1036-1039, 1047-1050, 1059-1062,1082-1085, and 1091-1094 of SEQ ID NO: 36; three predicted tyrosinekinase phosphorylation sites (PS00007) located at about amino acids577-584, 698-706, and 881-888 of SEQ ID NO: 36; eleven predictedN-myristoylation sites (PS00008) located at about amino acids 47-52,286-291, 368-373, 383-388, 467-472, 488-493, 598-603, 851-856, 871-876,994-999, and 1070-1075 of SEQ ID NO: 36; two predicted amidation site(PS00009) located at about amino acids 452-455 and 747-750 of SEQ ID NO:36; one predicted protein kinases ATP-binding region signature site(PS00107) located at about amino acids 731-739 of SEQ ID NO: 36; onetyrosine protein kinase specific active-site sign (PS00109) located atabout amino acids 888-900 of SEQ ID NO: 36; and one receptor tyrosinekinase class V signature 1 site (PS00790) located at about amino acids286-302 of SEQ ID NO: 36.

[0196] For general information regarding PFAM identifiers, PS prefix andPF prefix domain identification numbers, refer to Sonnhammer et al.(1997) Protein 28:405-420. The ephrin receptor ligand binding domain ofhuman 16658 (amino acids 128 to 301 of SEQ ID NO: 36) aligns with aconsensus amino acid sequence derived from a hidden Markov model (HMM)from PFAM (SEQ ID NO: 44).

[0197] The protein kinase domain of human 16658 (amino acids 725 to 1021of SEQ ID NO: 36) aligns with a consensus amino acid sequence derivedfrom a hidden Markov model (HMM) from PFAM(SEQ ID NO: 45).

[0198] A BLAST alignment of human 16658 with a consensus amino acidsequence derived from a ProDomain “receptor kinase tyrosine-proteinephrin precursor transferase ATP-binding phosphorylation type-Atransmembrane” (Release 2001.1) shows amino acid residues 1 to 180 ofthe 181 amino acid consensus sequence (SEQ ID NO: 46) aligns with the“receptor kinase tyrosine-protein ephrin precursor transferaseATP-binding phosphorylation type-A transmembrane” domain of human 16658,amino acid residues 128 to 301 of SEQ ID NO: 36.

[0199] Another BLAST alignment of human 16658 with a consensus aminoacid sequence derived from a ProDomain “receptor kinase tyrosine-proteinprecursor ephrin transferase ATP-binding phosphorylation type-Atransmembrane” (Release 2001.1) shows amino acid residues 1 to 127 ofthe 128 amino acid consensus sequence (SEQ ID NO: 47) aligns with the“receptor kinase tyrosine-protein precursor ephrin transferaseATP-binding phosphorylation type-A transmembrane” domain of human 16658,amino acid residues 411 to 534 of SEQ ID NO: 36.

[0200] Another BLAST alignment of human 16658 with a consensus aminoacid sequence derived from a ProDomain “receptor tyrosine-protein kinasetransm precursor ephrin EHK-2 kinase-2 type-A phosphorylation” (Release2001.1) shows amino acid residues 1 to 50 of the 50 amino acid consensussequence (SEQ ID NO: 48) aligns with the “receptor tyrosine-proteinkinase transm precursor ephrin EHK-2 kinase-2 type-A phosphorylation”domain of human 16658, amino acid residues 790 to 839 of SEQ ID NO: 36.

[0201] A BLAST alignment of human 16658 with a consensus amino acidsequence derived from a ProDomain “receptor kinase tyrosine-proteinprecursor ephrin ATP-binding transferase phosphorylation type-Atransmembrane” (Release 2001.1) shows amino acid residues 15 to 73 ofthe 74 amino acid consensus sequence (SEQ ID NO: 49) aligns with the“receptor kinase tyrosine-protein precursor ephrin ATP-bindingtransferase phosphorylation type-A transmembrane” domain of human 16658,amino acid residues 354 to 410 of SEQ ID NO: 36.

[0202] A BLAST alignment of human 16658 with a consensus amino acidsequence derived from a ProDomain “kinase tyrosine-protein repeat janusdomain phosphorylation ATP-binding SH2” (Release 2001.1) shows aminoacid residues 1 to 178 of the 179 amino acid consensus sequence (SEQ IDNO: 50), aligns with the “kinase tyrosine-protein repeat janus domainphosphorylation ATP-binding SH2e” domain of human 16658, amino acidresidues 843 to 1017 of SEQ ID NO: 36.

[0203] A BLAST alignment of human 16658 with a consensus amino acidsequence derived from a ProDomain “receptor kinase tyrosine-proteinprecursor ephrin transferase ATP-binding phosphorylation transmembranetype-A” (Release 2001.1) shows amino acid residues 28 to 82 of the 83amino acid consensus sequence (SEQ ID NO: 51) aligns with the “receptorkinase tyrosine-protein precursor ephrin transferase ATP-bindingphosphorylation transmembrane type-A” domain of human 16658, amino acidresidues 668 to 723 of SEQ ID NO: 36.

[0204] Human 14223

[0205] The present invention is based, in part, on the discovery of anovel human kinase, referred to herein as “14223”.

[0206] The human 14223 sequence (SEQ ID NO: 38), which is approximately2466 nucleotides long including untranslated regions, contains apredicted methionine-initiated coding sequence of about 1542 nucleotides(nucleotides 437-1978 of SEQ ID NO: 38; 1-1542 of SEQ ID NO: 40), notincluding the terminal codon. The coding sequence encodes a 514 aminoacid protein (SEQ ID NO: 39).

[0207] This mature protein form is approximately 514 amino acid residuesin length (from about amino acid 1 to amino acid 514 of SEQ ID NO: 39).Human 14223 contains the following regions or other structural features:a predicted kinase domain located at about amino acid residues 116-381of SEQ ID NO: 39.

[0208] A hydropathy plot of human 14223 was performed. Polypeptides ofthe invention include fragments which include: all or part of ahydrophobic sequence, e.g., the sequence from about amino acid 220 to230, from about 285 to 295, and from about 310 to 320 of SEQ ID NO: 39;all or part of a hydrophilic sequence, e.g., the sequence from aboutamino acid 60 to 100, from about 205 to 215, and from about 400 to 460of SEQ ID NO: 39; a sequence which includes a Cys, or a glycosylationsite.

[0209] The 14223 protein also includes the following domains: fourN-glycosylation sites (PS00001) located at about amino acids 95-98,213-216, 411-414, and 438-441 of SEQ ID NO: 39; three cAMP- andcGMP-dependent protein kinase phosphorylation site (PS00004) located atabout amino acids 8-11, 84-87, and 271-274 of SEQ ID NO: 39; twelvepredicted protein kinase C phosphorylation sites (PS00005) located atabout amino acids 10-12, 20-22, 29-31, 70-72, 134-136, 169-171, 184-186,371-373, 388-390, 459-461, 473-475, and 510-512 of SEQ ID NO: 39;eighteen predicted casein kinase II phosphorylation sites (PS00006)located at about amino 4-7, 20-23, 71-74, 80-83, 134-137, 211-214,249-252, 274-277, 296-299, 326-329, 349-352, 371-374, 407-410, 412-415,420-423, 440-443, 450-453, and 459-462 of SEQ ID NO: 39; two predictedN-myristoylation sites (PS00008) located at about amino acids 49-54 and383-388 of SEQ ID NO: 39; one predicted protein kinases ATP-bindingregion signature site (PS00107) located at about amino acids 122-130 ofSEQ ID NO: 39; one serine/threonine protein kinases active-site sign(PS00108) located at about amino acids 234-246 of SEQ ID NO: 39.

[0210] For general information regarding PFAM identifiers, PS prefix andPF prefix domain identification numbers, refer to Sonnhammer et al.(1997) Protein 28:405-420.

[0211] The protein kinase domain of human 14223 (amino acids 116 to 381of SEQ ID NO: 39) aligns with a consensus amino acid sequence derivedfrom a hidden Markov model (HMM) from PFAM (SEQ ID NO: 52).

[0212] A BLAST alignment of human 14223 with a consensus amino acidsequence derived from a ProDomain “kinase serine/threonine-proteintransferase receptor ATP-binding 2.7.1.—tyrosine-protein phosphorylationprecursor” (Release 2001.1) shows that amino acid residues 254 to 301,136 to 235, 51 to 184, 370 to 409, 6 to 85, and 344 to 370 of the 424amino acid consensus sequence (SEQ ID NOs: 53-58) align with the “kinaseserine/threonine-protein transferase receptor ATP-binding2.7.1.—tyrosine-protein phosphorylation precursor” domains of human14223, found from amino acid residues 285 to 329, 199 to 286, 124 to245, 293 to 323, 116 to 194, and 351 to 377 of SEQ ID NO: 39.

[0213] A BLAST alignment of human 14223 with a consensus amino acidsequence derived from a ProDomain “serine/threonine similar kinasekinases serine/threonine-protein” (Release 2001.1) shows that amino acidresidues 353 to 514 and 90 to 230 of the 717 amino acid consensussequence (SEQ ID NOs: 59-60) align with the “serine/threonine similarkinase kinases serine/threonine-protein” domains of human 14223, foundfrom amino acid residues 308 to 463 and 122 to 249 of SEQ ID NO: 39.

[0214] Human 16002

[0215] The present invention is based, in part, on the discovery of anovel human kinase, referred to herein as “16002”.

[0216] The human 16002 sequence (SEQ ID NO: 41), which is approximately2711 nucleotides long including untranslated regions, contains apredicted methionine-initiated coding sequence of about 1683 nucleotides(nucleotides 198-1880 of SEQ ID NO: 41; 1-1683 of SEQ ID NO: 43), notincluding the terminal codon. The coding sequence encodes a 561 aminoacid protein (SEQ ID NO: 42).

[0217] This mature protein form is approximately 561 amino acid residuesin length (from about amino acid 1 to amino acid 561 of SEQ ID NO: 42).Human 16002 contains the following regions or other structural features:a predicted kinase domain located at about amino acid residues 128-409of SEQ ID NO: 42; and a predicted transmembrane domain which extendsfrom about amino acid residue 336-354 of SEQ ID NO: 42.

[0218] The 16002 protein also includes the following domains: oneN-glycosylation site (PS00001) located at about amino acids 147-150 ofSEQ ID NO: 42; three cAMP- and cGMP-dependent protein kinasephosphorylation site (PS00004) located at about amino acids 71-74,105-108, and 455-458 of SEQ ID NO: 42; six predicted protein kinase Cphosphorylation sites (PS00005) located at about amino acids 58-60,69-71, 100-102, 160-162, 330-332, and 437-439 of SEQ ID NO: 42; eightpredicted casein kinase II phosphorylation sites (PS00006) located atabout amino 26-29, 74-77, 82-85, 117-120, 419-422, 425-428, 430-433, and557-560 of SEQ ID NO: 42; four predicted N-myristoylation sites(PS00008) located at about amino acids 178-183, 326-331, 515-520, and525-530 of SEQ ID NO: 42; one predicted ATP/GTP-binding site motif A(P-loop) (PS00017) located at about amino acids 485-492; one predictedprotein kinases ATP-binding region signature site (PS00107) located atabout amino acids 134-142 of SEQ ID NO: 42; and one serine/threonineprotein kinases active-site sign (PS00108) located at about amino acids271-283 of SEQ ID NO: 42.

[0219] For general information regarding PFAM identifiers, PS prefix andPF prefix domain identification numbers, refer to Sonnhammer et al.(1997) Protein 28:405-420

[0220] Polypeptides of the invention include fragments which include:all or part of a hydrophobic sequence, e.g., the sequence from aboutamino acid 255 to 265, from about 330 to 350, and from about 530 to 550of SEQ ID NO: 42; all or part of a hydrophilic sequence, e.g., thesequence from about amino acid 30 to 50, from about 170 to 185, and fromabout 455 to 475 of SEQ ID NO: 42; a sequence which includes a Cys, or aglycosylation site.

[0221] The protein kinase domain of human 16002 (amino acids 128 to 409of SEQ ID NO: 42) aligns with a consensus amino acid sequence derivedfrom a hidden Markov model (HMM) from PFAM (SEQ ID NO: 61).

[0222] A BLAST alignment of human 16002 with a consensus amino acidsequence derived from a ProDomain “kinase Ca2/calmodulin-dependentphosphorylase serine threonine hydroxyalkyl-protein B calcium/calmodulinalpha glycogen” (Release 2001.1) shows amino acid residues 1 to 80 ofthe 80 amino acid consensus sequence (SEQ ID NO: 62) aligns with the“kinase Ca2/calmodulin-dependent phosphorylase serine threoninehydroxyalkyl-protein B calcium/calmodulin alpha glycogen” domain ofhuman 16002, amino acid residues 1 to 80 of SEQ ID NO: 42.

[0223] A BLAST alignment of human 16002 with a consensus amino acidsequence derived from a ProDomain “kinase Ca2/calmodulin-dependent betaalpha synthase phosphorylase serine threonine calcium/calmodulin”(Release 2001.1) shows amino acid residues 1 to 61 of the 61 amino acidconsensus sequence (SEQ ID NO: 63) aligns with the “kinaseCa2/calmodulin-dependent beta alpha synthase phosphorylase serinethreonine calcium/calmodulin” domain of human 16002, amino acid residues403 to 463 of SEQ ID NO: 42.

[0224] A BLAST alignment of human 16002 with a consensus amino acidsequence derived from a ProDomain “kinase calcium/calmodulinalpha-dependent” (Release 2001.1). shows amino acid residues 1 to 47 ofthe 47 amino acid consensus sequence (SEQ ID NO: 64), aligns with the“kinase calcium/calmodulin alpha-dependent” domain of human 16002, aminoacid residues 81 to 127 of SEQ ID NO: 42.

[0225] A BLAST alignment of human 16002 with a consensus amino acidsequence derived from a ProDomain “kinase Ca2/calmodulin-dependentphosphorylase serinethreonine hydroxyalkyl-protein B calcium/calmodulinalpha glycogen” (Release 2001.1) shows amino acid residues 1 to 36 ofthe 42 amino acid consensus sequence (SEQ ID NO: 65) aligns with the“kinase Ca2/calmodulin-dependent phosphorylase serine threoninehydroxyalkyl-protein B calcium/calmodulin alpha glycogen” domain ofhuman 16002, amino acid residues 464 to 499 of SEQ ID NO: 42.

[0226] The 16658, 14223, and 16002 proteins contain a significant numberof structural characteristics in common with members of the kinasefamily. The term “family” when referring to the protein and nucleic acidmolecules of the invention means two or more proteins or nucleic acidmolecules having a common structural domain or motif and havingsufficient amino acid or nucleotide sequence homology as defined herein.Such family members can be naturally or non-naturally occurring and canbe from either the same or different species. For example, a family cancontain a first protein of human origin as well as other distinctproteins of human origin, or alternatively, can contain homologues ofnon-human origin, e.g., rat or mouse proteins. Members of a family canalso have common functional characteristics.

[0227] The present invention is based, at least in part, on thediscovery of novel molecules, referred to herein as “16658, 14223, and16002” nucleic acid and polypeptide molecules, which play a role in orfunction in the transduction of signals for cell proliferation,differentiation and apoptosis. In one embodiment, the 16658, 14223, and16002 molecules modulate the activity of one or more proteins involvedin cellular growth or differentiation, e.g., cell growth ordifferentiation. In another embodiment, the 16658, 14223, and 16002molecules of the present invention are capable of modulating thephosphorylation state of 16658, 14223, and 16002 molecules or one ormore proteins involved in cellular growth or differentiation.

[0228] 16022 has homology to rat calcium/calmodulin-dependent proteinkinase kinase (CaMKK) alpha. As such, without being bound by theory,16002 is expected to be a CaMKK that mediates responses in differentpain states of BDNF, the growth factor of the neurotrophin family thatis upregulated in nociceptive neurons after axotomy and CCI and releasedinto the dorsal horn of the spinal cord. CaMKK alpha phosphorylates CaMKI and IV that regulate transcription. Itself is negatively regulated byPKA. In the brain, CaMKK alpha blocks apoptosis-induced by increase ofintracellular Ca++ levels after NMDA receptor stimulation. NMDAreceptors are very important players in the modulation of pain in thespinal cord. In addition, CaMKIV, a substrate for CaMKK alpha, isphosphorylated after BDNF exposure.

[0229] As used herein, the term “protein kinase” includes a protein orpolypeptide which is capable of modulating its own phosphorylation stateor the phosphorylation state of another protein or polypeptide. Proteinkinases can have a specificity for (i.e., a specificity tophosphorylate) serine/threonine residues, tyrosine residues, or bothserine/threonine and tyrosine residues, e.g., the dual specificitykinases. As referred to herein, protein kinases preferably include acatalytic domain of about 200-400 amino acid residues in length,preferably about 250-300 amino acid residues in length, or morepreferably about 265-296 amino acid residues in length, which includespreferably 5-20, more preferably 5-15, or preferably 11 highly conservedmotifs or subdomains separated by sequences of amino acids with reducedor minimal conservation. Specificity of a protein kinase forphosphorylation of either tyrosine or serine/threonine can be predictedby the sequence of two of the subdomains (VIb and VIII) in whichdifferent residues are conserved in each class (as described in, forexample, Hanks et al. (1988) Science 241:42-52) the contents of whichare incorporated herein by reference). These subdomains are alsodescribed in further detail herein.

[0230] Protein kinases play a role in signaling pathways associated withcellular growth. For example, protein kinases are involved in theregulation of signal transmission from cellular receptors, e.g.,growth-factor receptors; entry of cells into mitosis; and the regulationof cytoskeleton function, e.g., actin bundling. Thus, the 16658, 14223,and 16002 molecules of the present invention may be involved in: 1) theregulation of transmission of signals from cellular receptors, e.g.,growth factor receptors; 2) the modulation of the entry of cells intomitosis; 3) the modulation of cellular differentiation; 4) themodulation of cell death; and 5) the regulation of cytoskeletonfunction.

[0231] Inhibition or over stimulation of the activity of protein kinasesinvolved in signaling pathways associated with cellular growth can leadto perturbed cellular growth, which can in turn lead to cellular growthrelated disorders. As used herein, a “cellular growth related disorder”includes a disorder, disease, or condition characterized by aderegulation, e.g., an upregulation or a downregulation, of cellulargrowth. Cellular growth deregulation may be due to a deregulation ofcellular proliferation, cell cycle progression, cellular differentiationand/or cellular hypertrophy.

[0232] The present invention is based, at least in part, on thediscovery of novel molecules, referred to herein as 16658, 14223, and16002 protein and nucleic acid molecules, which comprise a family ofmolecules having certain conserved structural and functional features.

[0233] One embodiment of the invention features 16658, 14223, and 16002nucleic acid molecules, preferably human 16658, 14223, and 16002molecules, e.g., 16658, 14223, and 16002. The 16658, 14223, and 16002nucleic acid and protein molecules of the invention are described infurther detail in the following subsections.

[0234] A 16658, 14223, and 16002 polypeptide can include a “kinasedomain” or regions homologous with a “kinase domain”

[0235] As used herein, the term “kinase domain” includes an amino acidsequence of about 100-400 amino acid residues in length and having a bitscore for the alignment of the sequence to the kinase domain (HMM) of atleast 8. Preferably, a kinase domain includes at least about 100-350amino acids, more preferably about 250-300 amino acid residues, or about265-396 amino acids and has a bit score for the alignment of thesequence to the kinase domain (HMM) of at least 16 or greater. Thekinase domain (amino acids 725-1021, 116-381, and 128-409 of SEQ ID NO:36, SEQ ID NO: 39, and SEQ ID NO: 42, respectively) of human 16658,14223, and 16002 were aligned with a consensus amino acid sequencederived from a hidden Markov model.

[0236] In a preferred embodiment 16658, 14223, and 16002 polypeptides orproteins have a “kinase domain” or a region which includes at leastabout 200-350 more preferably about 250-300 or 265-396 amino acidresidues and has at least about 60%, 70%, 80%, 90%, 95%, 99%, or 100%homology with an “kinase domain,” e.g., the kinase domain of human16658, 14223, and 16002 (e.g., amino acid residues 725-1021, 116-381,and 128-409 of SEQ ID NO: 36, SEQ ID NO: 39, and SEQ ID NO: 42,respectively).

[0237] To identify the presence of a “kinase domain” in a 16658, 14223or 16002 protein sequence, and make the determination that a polypeptideor protein of interest has a particular profile, the amino acid sequenceof the protein can be searched against a database of HMMs (e.g., thePfam database, release 2.1) using the default parameters. For example,the hmmsf program, which is available as part of the HMMER package ofsearch programs, is a family specific default program for MILPAT0063 anda score of 15 is the default threshold score for determining a hit.Alternatively, the threshold score for determining a hit can be lowered(e.g., to 8 bits). A description of the Pfam database can be found inSonhammer et al., (1997) Proteins 28(3):405-420 and a detaileddescription of HMMs can be found, for example, in Gribskov et al.,(1990) Meth. Enzymol. 183:146-159; Gribskov et al., (1987) Proc. Natl.Acad. Sci. USA 84:4355-4358; Krogh et al., (1994) J. Mol. Biol.235:1501-1531; and Stultz et al., (1993) Protein Sci. 2:305-314, thecontents of which are incorporated herein by reference. A search wasperformed against the HMM database resulting in the identification of a“kinase domain” in the amino acid sequence of human 16658 at aboutresidues 725 to 1021 of SEQ ID NO: 36; of human 14223 at about residues116 to 381 of SEQ ID NO: 39; or of human 16002 at about residues 128 to409 of SEQ ID NO: 42.

[0238] For further identification of domains in a 16658, 14223, and16002 protein sequence, and make the determination that a polypeptide orprotein of interest has a particular profile, the amino acid sequence ofthe protein can be searched against a database of domains, e.g., theProDom database (Corpet et al. (1999), Nucl. Acids Res. 27:263-267). TheProDom protein domain database consists of an automatic compilation ofhomologous domains. Current versions of ProDom are built using recursivePSI-BLAST searches (Altschul S F et al. (1997) Nucleic Acids Res.25:3389-3402; Gouzy et al. (1999) 23:333-340) of the SWISS-PROT 38 andTREMBL protein databases. The database automatically generates aconsensus sequence for each domain. A BLAST search was performed againstthe HMM database resulting in the identification of a “kinase” domain(s)in the amino acid sequence of human 16658 at about residues 128 to 301,411 to 534, 790 to 839, 354 to 410, 843 to 1017, 668 to 723 of SEQ IDNO: 36 having 71%, 58%, 98%, 54%, 28% and 60% identity over thoseresidues respectively; of human 14223 at about residues 285 to 329, 199to 286, 124 to 245, 293 to 323, 116 to 194, and 351 to 377 (six localalignments) of SEQ ID NO: 39 having 52%, 29%, 21%, 35%, 31% and 25%identity over those residues respectively; 308 to 463 and 122 to 249(two local alignments) of SEQ ID NO: 39 having 25% identity over thoseresidues; and of human 16002 at about residues 1 to 80, 403 to 463, 81to 127, or 464 to 499 of SEQ ID NO: 42 having 83%, 78%, 78%, and 94%,identity over those residues respectively.

[0239] The 16658, 14223, and 16002 proteins include an ATP-bindingregion signature. Preferably, the ATP-binding region signature includesthe following amino acid consensus sequence having Prosite signature asPS00107, or sequences homologous thereto:[LIV]-G-{P}-G-{P}-[FYWMGSTNH]-[SGA]-{PW}-[LIVCAT]-{PD}-x-[GSTACLIVMFY]-x(5,18)-[LIVMFYWCSTAR]-[AIVP]-[LWVMFAGCKR]—K[K binds ATP] (SEQ ID NO: 66). In the above conserved motif, and othermotifs described herein, the standard IUPAC one-letter code for theamino acids is used. Each element in the pattern is separated by a dash(-); square brackets ([]) indicate the particular residues that areaccepted at that position; x indicates that any residue is accepted atthat position; and numbers in parentheses (( )) indicate the number ofresidues represented by the accompanying amino acid. The ATP-bindingregion of 16658 is found in the C-terminal cytoplasmic domain. TheATP-binding region of 16002 is found in the N-terminal cytoplasmicdomain

[0240] A 16658 polypeptide can also include a “tyrosine protein kinasespecific active-site signature”. Preferably, the tyrosine protein kinasespecific active-site signature includes the following amino acidconsensus sequence having Prosite signature as PS00109, or sequenceshomologous thereto:[LIVMFYC]-x-[HY]-x-D-[LIVMFY]—[RSTAC]-x(2)-N-[LIVMFYC](3) [D is anactive site residue] (SEQ ID NO: 67). The tyrosine protein kinasespecific active-site signature for 16658 is found in the C-terminalcytoplasmic domain. A 14223 or 16002 polypeptide can also include a“serine/threonine protein kinases active-site signature”. Preferably,the serine/threonine protein kinases active-site signature includes thefollowing amino acid consensus sequence having Prosite signature asPS00109, or sequences homologous thereto:[LVWMFYC]-x-[HY]-x-D-[LIVMFY]—K-x(2)-N-[LIVMFYCT](3) [D is an activesite residue] (SEQ ID NO: 68). The serine/threonine protein kinasesactive-site signature for 14223 is found in a hydrophilic region of thepolypeptide. The serine/threonine protein kinases active-site signaturefor the 16002 polypeptide is found in N-terminal cytoplasmic domain.

[0241] A 16658 polypeptide can also include a “receptor tyrosine kinaseclass V signature 1”. Preferably, the receptor tyrosine kinase class Vsignature 1 includes the following amino acid consensus sequence havingProsite signature as PS00790, or sequences homologous thereto:F-x-[DN]-x-[GAW]-[GA]-C-[LIVM]-[SA]-[LIVM](2)-[SA]-[LV]—[KRHQ]-[LIVA]-x(3)-[KR]—C—[PSAW] (SEQ ID NO: 69). A 16658polypeptide can also include a “receptor tyrosine kinase class Vsignature 2”. Preferably, the receptor tyrosine kinase class V signature2 includes the following amino acid consensus sequence having Prositesignature as PS00791, or sequences homologous thereto:C-x(2)-[DE]-G-[DEQ]-W-x(2,3)-[PAQ]-[LIVMT]-[GT]-x-C-x-C-x(2)-G-[HFY]-[EQ](SEQ ID NO: 70). The receptor tyrosine kinase class V signatures 1 and 2for 16658 are found in the extracellular loop.

[0242] A 16658 polypeptide can also include a “EGF-like domain signature2”. Preferably, the EGF-like domain signature 2 includes the followingamino acid consensus sequence having Prosite signature as PS01186, orsequences homologous thereto: C-x-C-x(2)-[GP]—[FYW]-x(4,8)-C (SEQ ID NO:71). The EGF-like domain signature 2 for 16658 is found in theextracellular loop.

[0243] A 16002 polypeptide can also include an “ATP/GTP-binding sitemotif A (P-loop)”. Preferably, the ATP/GTP-binding site motif A (P-loop)includes the following amino acid consensus sequence having Prositesignature as PS00017, or sequences homologous thereto:[AG]-x(4)-G-K—[ST] (SEQ ID NO: 72). The ATP/GTP-binding site motif A(P-loop) for 16002 is found in the extracellular loop.

[0244] In one embodiment, a 16658 protein includes at least one andpreferably two transmembrane domains and a 16002 protein includes atleast one transmembrane domain. As used herein, the term “transmembranedomain” includes an amino acid sequence of about 10 to 40 amino acidresidues in length and spans the plasma membrane. Transmembrane domainsare rich in hydrophobic residues, e.g., at least 50%, 60%, 70%, 80%,90%, 95% or more of the amino acids of a transmembrane domain arehydrophobic, e.g., leucines, isoleucines, tyrosines, or tryptophans.Transmembrane domains typically have alpha-helical structures and aredescribed in, for example, Zagotta, W. N. et al., (1996) Annual Rev.Neurosci. 19:235-263, the contents of which are incorporated herein byreference.

[0245] In a preferred embodiment, a 16658 protein includes at least oneand preferably two transmembrane domains and a 16002 protein includes atleast one transmembrane domain or a region which includes at least orregions which include at least about 12 to 35 more preferably about 14to 30 or 15 to 25 amino acid residues or 16, 18, 20, 22, 23, 24, 25, or30 amino acid residues and has at least about 60%, 70% 80% 90% 95%, 99%,or 100% homology with a “transmembrane domain,” e.g., at least onetransmembrane domain of human 16658 or 16002 (e.g., amino acid residues103-119 and 642-665 of SEQ ID NO: 36, or amino acid residues 336-354 ofSEQ ID NO: 42). The transmembrane domain of human 16658 and 16002 can bevisualized in a hydropathy plot as regions of about 15 to 25 amino acidswhere the hydropathy trace is mostly above the horizontal line.

[0246] To identify the presence of a “transmembrane” domain in a 16658or 16002 protein sequence, and make the determination that a polypeptideor protein of interest has a particular profile, the amino acid sequenceof the protein can be analyzed by a transmembrane prediction method thatpredicts the secondary structure and topology of integral membraneproteins based on the recognition of topological models (MEMSAT, Joneset al., (1994) Biochemistry 33:3038-3049).

[0247] A mature 16658 protein includes at least one, two, preferablythree “non-transmembrane regions” and a mature 16002 protein includes atleast one, and preferably two “non-transmembrane regions.” As usedherein, the term “non-transmembrane region” includes an amino acidsequence not identified as a transmembrane domain. The non-transmembraneregions in 16658 or 16002 are located at about amino acids residues1-102, 120-641, and 666-1130 of SEQ ID NO: 36 or 1-335 and 356-561 ofSEQ ID NO: 42.

[0248] The non-transmembrane regions of 16658 include at least onepreferably two cytoplasmic regions, and non-transmembrane regions of16002 include at least one cytoplasmic region. When located at theN-terminus, the cytoplasmic region is referred to herein as the“N-terminal cytoplasmic domain.” As used herein, an “N-terminalcytoplasmic domain” includes an amino acid sequence having about 1-400,preferably about 30-75, more preferably about 50-350, or even morepreferably about 102-335 amino acid residues in length and is locatedinside of a cell or within the cytoplasm of a cell. The C-terminal aminoacid residue of an “N-terminal cytoplasmic domain” is adjacent to anN-terminal amino acid residue of a transmembrane domain in a 16658 or16002 protein. For example, an N-terminal non-transmembrane domain islocated at about amino acid residues 1-102 of SEQ ID NO: 36.

[0249] In a preferred embodiment, a polypeptide or protein has anN-terminal cytoplasmic domain or a region which includes at least about5, preferably about 1 to 400, and more preferably about 1 to 350 aminoacid residues and has at least about 60%, 70% 80% 90% 95%, 99%, or 100%homology with an “N-terminal cytoplasmic domain,” e.g., the N-terminalcytoplasmic domain of human 16658 (e.g., residues 1 to 102 of SEQ ID NO:36).

[0250] In another embodiment, a cytoplasmic region of a 16658 proteincan include the C-terminus and can be a “C-terminal cytoplasmic domain,”also referred to herein as a “C-terminal cytoplasmic tail.” As usedherein, a “C-terminal cytoplasmic domain” includes an amino acidsequence having a length of at least about 10, preferably about 1-500,preferably about 100-490, preferably about 150-480, more preferablyabout 200-464 amino acid residues and is located inside of a cell orwithin the cytoplasm of a cell. The N-terminal amino acid residue of a“C-terminal cytoplasmic domain” is adjacent to a C-terminal amino acidresidue of a transmembrane domain in a 16658 protein. For example, aC-terminal cytoplasmic domain is located at about amino acid residues666-1130 of SEQ ID NO: 36.

[0251] In a preferred embodiment, a 16658 polypeptide or protein has aC-terminal cytoplasmic domain or a region which includes at least about5, preferably about 10 to 200, and more preferably about 150 to 200amino acid residues and has at least about 60%, 70% 80% 90% 95%, 99%, or100% homology with a C-terminal cytoplasmic domain,” e.g., theC-terminal cytoplasmic domain of human 16658 (e.g., residues 666-1130 ofSEQ ID NO: 36).

[0252] In another embodiment, a 16658 protein includes at least onenon-cytoplasmic loop. As used herein, a “non-cytoplasmic loop” includesan amino acid sequence located outside of a cell or within anintracellular organelle. Non-cytoplasmic loops include extracellulardomains (i.e., outside of the cell) and intracellular domains (i.e.,within the cell). When referring to membrane-bound proteins found inintracellular organelles (e.g., mitochondria, endoplasmic reticulum,peroxisomes microsomes, vesicles, endosomes, and lysosomes),non-cytoplasmic loops include those domains of the protein that residein the lumen of the organelle or the matrix or the intermembrane space.For example, a “non-cytoplasmic loop” can be found at about amino acidresidues 120-641 of SEQ ID NO: 36.

[0253] In a preferred embodiment, a 16658 polypeptide or protein has atleast one non-cytoplasmic loop or a region which includes at least about4, preferably about 5 to 600, more preferably about 6 to 550 amino acidresidues and has at least about 60%, 70% 80% 90% 95%, 99%, or 100%homology with a “non-cytoplasmic loop,” e.g., at least onenon-cytoplasmic loop of human 16658 (e.g., residues 120-641 of SEQ IDNO: 36).

[0254] As the 16658, 14223, and 16002 polypeptides of the invention maymodulate 16658-, 14223-, and 16002-mediated activities, they may beuseful for developing novel diagnostic and therapeutic agents for16658-, 14223-, and 16002-mediated or related disorders. Accordingly,16658, 14223, and 16002 proteins may mediate various disorders,including cellular proliferative and/or differentiative disorders, braindisorders, pain or metabolic disorders.

[0255] The 16658, 14223, and 16002 nucleic acid and protein of theinvention can be used to treat and/or diagnose a variety ofproliferative disorders, e.g., such disorders include hematopoieticneoplastic disorders.

[0256] Gene Expression of 16658 and 16002

[0257] TaqMan real-time quantitative RT-PCR is used to detect thepresence of RNA transcript corresponding to human 16658 or 16002relative to a no template control in a panel of human tissues or cells.

[0258] It was found that the highest expression of 16658 orthologs areexpressed in normal ovary cell lines in an oncology phase II plate asshown in the following Table 12. TABLE 12 16658 Expression in OncologyPhase II plate Tissue Type Mean 16658 β 2 Mean ∂∂ Ct Expression PIT 400Breast N 40 19.47 20.53 0 PIT 372 Breast N 40 20.18 19.82 0 CHT 558Breast N 40 19.05 20.95 0 CLN 168 Breast T: IDC 40 19.61 20.39 0 MDA 304Breast T: MD- 39.36 18.51 20.85 0 IDC NDR 57 Breast T: IDC- 40 19.0320.97 0 PD NDR 132 Breast T: IDC/ 40 20.78 19.22 0 ILC CHT 562 Breast T:IDC 39.31 18.8 20.5 0 NDR 12 Breast T 36 21.84 14.16 0 PIT 208 Ovary N27.6 18.53 9.07 1.86 CHT 620 Ovary N 32.58 19.47 13.11 0.11 CLN 03 OvaryT 35.49 19.43 16.07 0 CLN 17 Ovary T 39.73 19.95 19.78 0 MDA 25 Ovary T40 21.82 18.18 0 MDA 216 Ovary T 37.59 20.09 17.5 0 CLN 012 Ovary T38.48 21.16 17.32 0 MDA 185 Lung N 40 19.57 20.43 0 CLN 930 Lung N 4018.89 21.11 0 MDA 183 Lung N 40 18.06 21.95 0 MPI 215 Lung T--SmC 39.9219.05 20.88 0 MDA 259 Lung T- 40 19.95 20.05 0 PDNSCCL CHT 832 Lung T-40 18.98 21.02 0 PDNSCCL CHT 911 Lung T-SCC 37.59 19.32 18.27 0 MDA 262Lung T-SCC 37.15 22.34 14.81 0 CHT 211 Lung T-AC 40 19.17 20.83 0 MDA253 Lung T- 40 18.36 21.64 0 PDNSCCL NHBE 39.42 21.09 18.34 0 CHT 396Colon N 40 23.82 16.18 0 CHT 523 Colon N 36.09 18.77 17.32 0 CHT 452Colon N 40 17.4 22.6 0 CHT 382 Colon T: MD 40 18.19 21.81 0 CHT 528Colon T: MD 40 17.99 22.01 0 CLN 609 Colon T 39.51 18.77 20.73 0 CHT 372Colon T: MD- 40 19.41 20.59 0 PD NDR 217 Colon-Liver 39.8 18.61 21.19 0Met NDR 100 Colon-Liver 40 18.06 21.94 0 Met PIT 260 Liver N (female) 4017.02 22.98 0 ONC 102 Hemangioma 40 19.22 20.78 0 A24 HMVEC-Arr 37.6818.96 18.72 0 C48 HMVEC-Prol 38.31 20.68 17.62 0

[0259] As seen by these results, 16658 molecules have been found to beunderexpressed in some tumor cells, where the molecules may beinappropriately propagating either cell proliferation or cell survivalsignals. As such, activators of the 16658 molecules are useful for thetreatment of cancer, preferably ovarian cancer, and useful as adiagnostic.

[0260] It was found that the highest expression of 16658 orthologs inphase 1.5.1 expression of 16658 w/β2 is found in normal brain cortex andalso in brain hypothalamus as shown in the following Table 13. TABLE 13Phase 1.5.1 Expression of 16658 w/β2 Tissue Type Mean β 2 Mean ∂∂ CtExpression Artery normal 37.62 21.77 15.85 0 Aorta diseased 39.01 21.7717.23 0 Vein normal 40 19.7 20.31 0 Coronary SMC 38.19 22.4 15.79 0HUVEC 36.99 20.75 16.25 0 Hemangioma 37.32 19.04 18.29 0 Heart normal38.34 29.85 8.49 0 Heart CHF 38.87 19.26 19.61 0 Kidney 34.42 20.2 14.220.0524 Skeletal Muscle 40 22 18 0 Adipose normal 39.63 20.18 19.45 0Pancreas 39.73 21.28 18.45 0 primary osteoblasts 40 20.22 19.79 0Osteoclasts (diff) 40 17.22 22.78 0 Skin normal 40 21.95 18.05 0 Spinalcord normal 35.52 20.14 15.39 0 Brain Hypothalamus normal 30.54 21.78.83 2.1974 Nerve 39.85 21.81 18.05 0 Breast normal 40 20.03 19.97 0Breast tumor 40 20.3 19.7 0 Ovary Tumor 34.32 19.86 14.46 0.0444Prostate Normal 37.01 19.34 17.66 0 Prostate Tumor 33.24 20.34 12.90.1313 Salivary glands 38.98 19.57 19.41 0 Colon normal 34.03 17.9116.13 0.0139 Colon Tumor 39.34 18.36 20.98 0 Lung normal 38.15 17.5820.57 0 Lung tumor 39.68 19.72 19.97 0 Lung COPD 39.65 28.95 10.69 0Colon IBD 40 18.16 21.84 0 Liver normal 40 19.55 20.45 0 Liver fibrosis38.11 21.5 16.61 0 Spleen normal 39.62 18.73 20.88 0 Tonsil normal 39.6316.91 22.72 0 Lymph node normal 40 18.34 21.66 0 Small intestine normal38.42 30.05 8.37 0 Skin-Decubitus 40 20.39 19.61 0 Synovium 37.49 18.9118.57 0 BM-MNC 40 18.04 21.96 0 Activated PBMC 40 17.5 22.5 0Neutrophils 40 18.4 21.61 0 Megakaryocytes 40 18.09 21.91 0 Erythroid 4021 19 0 Brain Cortex normal 28.31 23.11 5.19 27.3939 DRG (Dorsal RootGanglion) 33.59 21.65 11.94 0.2554 Ovary normal 31.93 19.76 12.17 0.217

[0261] The highest levels of expression of 16658 orthologs in expressionof 16658 w/β2 (Table 14) and in pain human panel phase I (Table 15) wasfound in brain. 16002 was also expressed at much lower levels in spinalcord, DRG, thymus, salivary gland and trachea. TABLE 14 Expression of16002 w/β2 Tissue Type Mean β 2 Mean ∂∂ Ct Expression Artery normal38.79 21.54 7.25 0 Vein normal 32.73 19.97 12.76 0.1442 Aortic SMC EARLY28.18 20.94 7.24 6.6152 Coronary SMC 28.45 21.41 7.04 7.5726 StaticHUVEC 28.9 20.44 8.46 2.8398 Shear HUVEC 27.92 20.37 7.55 5.3361 Heartnormal 28.25 18.66 9.59 1.2975 Heart CHF 29.3 18.34 10.96 0.502 Kidney27.47 19.12 8.35 3.0754 Skeletal Muscle 31.7 21.29 10.41 0.7324 Adiposenormal 32.27 19.48 12.79 0.1417 Pancreas 30.33 20.44 9.89 1.0539 primaryosteoblasts 30.16 19.1 11.06 0.47 Osteoclasts (diff) 29.45 16.77 12.680.1529 Skin normal 30.22 20.68 9.54 1.3433 Spinal cord normal 29.1319.47 9.66 1.2361 Brain Cortex normal 23.04 20.75 2.28 205.8978 BrainHypothalamus normal 27.03 21.25 5.78 18.2621 Nerve 34.86 24.16 10.70.6011 DRG (Dorsal Root Ganglion) 27.07 21.12 5.95 16.176 Glial Cells(Astrocytes) 28.18 21.9 6.29 12.8241 Glioblastoma 27.87 17.25 10.620.6354 Breast normal 29.34 19.52 9.82 1.1063 Breast tumor 26.34 17.918.43 2.8995 Ovary normal 29.27 19.8 9.46 1.415 Ovary Tumor 30.86 19.2211.64 0.3133 Prostate Normal 27.75 18.95 8.79 2.2513 Prostate Tumor25.32 16.34 8.97 1.9873 Epithelial Cells (Prostate) 29.62 20.36 9.261.631 Colon normal 28.68 17.66 11.02 0.4816 Colon Tumor 25.57 18.23 7.346.1936 Lung normal 30.5 17.28 13.23 0.1044 Lung tumor 26.75 17.41 9.341.5484 Lung COPD 28.23 17.9 10.33 0.7769 Colon IBD 29.56 16.81 12.750.1452 Liver normal 32.91 19.06 13.85 0.0677 Liver fibrosis 31.59 20.6710.91 0.5179 Dermal Cells - fibroblasts 28.26 19.29 8.97 1.9942 Spleennormal 29.64 19.12 10.52 0.681 Tonsil normal 27.81 16.56 11.25 0.4106Lymph node 29.51 18.22 11.3 0.398 Resting PBMC 30.27 19.47 10.8 0.5628Skin-Decubitus 28.75 20.12 8.63 2.5329 Synovium 28.93 18.57 10.36 0.7635BM-MNC (Bone marrow 26.46 16.51 9.95 1.011 mononuclear cells) ActivatedPBMC 28.18 15.37 12.82 0.1388

[0262] TABLE 15 16002 Human Panel Phase I Tissue Type 16002 β2.803 ∂ CtExpression Adrenal Gland 25.91 17.60 8.31 3.15 Brain 23.20 19.95 3.26104.75 Heart 28.94 18.08 10.86 0.54 Kidney 27.86 17.86 10.00 0.98 Liver29.25 18.08 11.17 0.44 Lung 28.16 16.28 11.88 0.27 Mammary Gland 27.3817.24 10.14 0.89 Pancreas 28.21 20.37 7.85 4.35 Placenta 33.31 18.1815.13 0.03 Prostate 30.26 16.90 13.36 0.10 Salivary Gland 26.38 18.497.89 4.22 Muscle 29.10 19.92 9.18 1.72 Sm. Intestine 27.59 18.05 9.541.35 Spleen 30.06 15.99 14.07 0.06 Stomach 28.18 17.64 10.55 0.67 Teste25.67 19.68 5.99 15.79 Thymus 26.28 17.56 8.72 2.37 Trachea 27.28 18.418.88 2.13 Uterus 27.08 18.54 8.54 2.69 Spinal Cord 28.49 18.69 9.80 1.12DRG 28.20 19.24 8.96 2.01 Skin 28.03 18.08 9.95 1.01

[0263] The following Table 16 showing the results of a TaqMan experimentwith rat panel phase I, showed a similar pattern of expression as thatof the human 16002 gene. This gene is also expressed in the SCG. TABLE16 12818 Rat Panel Phase I Tissue r12818 18S ∂ Ct Expression Brain 23.9212.85 11.07 0.47 Spinal Cord 23.77 12.86 10.91 0.52 DRG 25.27 13.6911.59 0.33 SCG 26.10 13.58 12.52 0.17 Hairy Skin 26.98 13.91 13.07 0.12Gastro Muscle 28.88 14.24 14.64 0.04 Heart 29.76 13.68 16.08 0.01 Kidney28.67 13.43 15.25 0.03 Liver 30.95 12.95 18.00 0.00 Lung 25.91 12.7113.20 0.11 Spleen 27.52 13.78 13.75 0.07 Aorta 28.78 14.20 14.58 0.04Adrenal Gland 25.46 13.35 12.12 0.23 Salivary Gland 27.47 13.15 14.330.05 Thyroid 26.47 14.37 12.10 0.23 Prostate 28.93 13.50 15.43 0.02Thymus 26.64 13.56 13.08 0.12 Trachea 28.04 14.37 13.67 0.08 Esophagus27.12 14.16 12.96 0.13 Duodenum 31.70 14.48 17.22 0.01 Diaphragm 29.6313.98 15.65 0.02

[0264] The following table, Table 17, shows the results of a TaqManexperiment with rat phase II and II panels. There is little or noregulation of this gene in animal models. TABLE 17 12818 Rat Panel PhaseII and III Tissue r12818 18S ∂ Ct Expression Naïve DRG 24.77 12.27 12.500.17 I DRG CCI 3 24.51 12.52 11.99 0.25 I DRG CCI 7 25.22 12.03 13.200.11 I DRG CCI 10 25.25 12.09 13.16 0.11 I DRG CCI 14 25.07 11.98 13.090.11 I DRG CCI 28 25.33 11.99 13.34 0.10 Naïve DRG 25.17 12.34 12.830.14 I DRG CFA 1 24.92 12.08 12.84 0.14 I DRG CFA 3 25.17 12.23 12.940.13 I DRG CFA 7 25.05 12.16 12.89 0.13 I DRG CFA 10 24.88 12.34 12.540.17 I DRG CFA 14 24.57 11.84 12.73 0.15 I DRG CFA 28 24.69 12.14 12.550.17 Naïve DRG 24.99 11.82 13.18 0.11 I DRG AXT 1 24.95 12.11 12.84 0.14I DRG AXT 3 25.24 12.30 12.94 0.13 I DRG AXT 7 25.57 12.15 13.43 0.09 IDRG AXT 14 25.27 11.99 13.29 0.10 Naïve SC 22.31 12.34 9.97 1.00 I SCCCI 3 22.80 12.63 10.17 0.87 I SC CCI 7 22.71 12.79 9.92 1.03 I SC CCI10 22.42 13.14 9.28 1.61 I SC CCI 14 22.33 12.12 10.22 0.84 I SC CCI 2822.47 13.07 9.40 1.48 Naïve SC 22.67 12.85 9.82 1.11 I SC CFA 1 22.9612.77 10.19 0.86 I SC CFA 3 22.75 12.45 10.31 0.79 I SC CFA 7 23.3012.37 10.93 0.51 I SC CFA 10 23.09 12.86 10.23 0.83 I SC CFA 14 23.1413.30 9.84 1.09 I SC CFA 28 23.03 12.97 10.06 0.94 Naïve SC 22.75 12.7110.04 0.95 I SC AXT 1 22.65 12.81 9.85 1.09 I SC AXT 3 23.26 12.51 10.750.58 I SC AXT 7 23.36 12.42 10.94 0.51 I SC AXT 14 22.41 13.34 9.07 1.86mAorta 38.01 14.41 23.60 0.00 mL4/5 DRG 34.11 13.69 20.42 0.00 mCerv DRG34.00 14.01 19.99 0.00 mL4/5 SC 28.77 12.79 15.98 0.02 mCerv · SC 28.9512.95 16.00 0.02 mSciatic 39.37 14.58 24.80 0.00 mPancreas 40.00 28.9611.04 0.47 SNS WT 32.44 13.23 19.21 0.00 SNS WT 31.22 12.66 18.56 0.00rDRG 26.62 13.64 12.99 0.12 rSC 28.40 15.21 13.19 0.11

[0265] In situ Hybridization of 16002

[0266] ISH experiment using a human probe showed that the 16002 gene isexpressed in human, monkey and rat cortex as well as in monkey and ratspinal cord and DRG. In the rat brain this gene is also expressed athigh levels in the hippocampus and at lower levels in the thalamus andin the basal ganglia. In the spinal cord, 16002 is expressed in laminaII of the dorsal horn as well as in laminae V—X. In the DRG, neuronsmainly of intermediate size are expressing this gene.

[0267] Human 50566 (G2RF)

[0268] The present invention is based, at least in part, on thediscovery of novel molecules, referred to herein as “Glyoxalase IIRelated Factor” or “G2RF” or “50566” nucleic acid and polypeptidemolecules, which are novel members of the glyoxalase system enzymefamily. These novel molecules are capable of metabolizing toxiccompounds (e.g., cytotoxin or other metabolites) in a cell, e.g., aheart, placenta, lung, liver, skeletal muscle, thymus, kidney, pancreas,testis, ovary, prostate, colon, or brain cell. By doing so, thesemolecules help maintain a proper equilibrium of toxic compounds in acell, thus preventing the occurrence of cellular damage.

[0269] As used herein, a “glyoxalase II related factor” includes aprotein or polypeptide which is involved in the metabolism of cytotoxinsand other metabolites, as well as in the regulation of their cellularlevels. As used herein, the terms “cytotoxins” and “metabolites” includecompounds which can be harmful or detrimental to a cell when present insufficient concentrations or quantities. Cytotoxins and metabolitesinclude those which arise from endogenous sources, e.g., the normalmetabolic processes of the cell such as the energetic metabolicpathways. Cytotoxins and metabolites may also enter the cell from theextracellular milieu. Cytotoxins and metabolites which enter the cellinclude those which originate from outside the organism (xenobioticcompounds). Examples of cytotoxins and metabolites includeoxaloaldehydes, hydrocarboxylic acids, pharmacological compounds (e.g.,chemotherapeutic compounds and anti-cancer drugs), oxidative compounds,glutathione-conjugates, energy metabolites, methylglyoxal, and the like.

[0270] As used herein, the phrase “regulation of cellular levels”includes cellular mechanisms involved in regulating and influencing thelevels (e.g., intracellular and/or extracellular levels) of cytotoxinsand metabolites (e.g., oxaloaldehydes and hydrocarboxylic acids orglutathione-conjugates). Such mechanisms include the conversion ofpotentially cytotoxic compounds into non-toxic or less toxic compounds,e.g., conversion of oxaloaldehydes (such as methylglyoxal or glutathioneconjugates) into hydrocarboxylic acids (such as lactate) in response tobiological cues, such as formation of nucleotide adjunct, modificationof amino acids, and oxidative stress. The maintenance of regulation ofcytotoxin and metabolite levels is particularly important for a cell'sability to function properly. Thus, the G2RF or 50566 molecules, byparticipating in the regulation of cytotoxin and metabolite levels, mayprovide novel diagnostic targets and therapeutic agents for controllingcytotoxin- and metabolite-associated disorders (e.g.,glyoxalase-associated disorders, oxaloaldehyde- andmethylglyoxal-associated disorders).

[0271] As used herein, the terms “cytotoxin-associated disorders” and“metabolite-associated disorders” include disorders, diseases, orconditions which are characterized by aberrant, e.g., upregulated,downregulated, or misregulated, cytotoxin and/or metabolite levels(e.g., oxaloacetate, hydroxycarboxylic acid, thioester compound, orglutathione-conjugated compound levels). Examples of such disorders mayinclude cardiovascular disorders, e.g., arteriosclerosis, ischemiareperfusion injury, restenosis, arterial inflammation, vascular wallremodeling, ventricular remodeling, rapid ventricular pacing, coronarymicroembolism, tachycardia, bradycardia, pressure overload, aorticbending, coronary artery ligation, vascular heart disease, atrialfibrillation, long-QT syndrome, congestive heart failure, sinus nodedysfunction, angina, heart failure, hypertension, atrial fibrillation,atrial flutter, dilated cardiomyopathy, idiopathic cardiomyopathy,myocardial infarction, coronary artery disease, coronary artery spasm,or arrhythmia.

[0272] Other examples of cytotoxin- and metabolite-associated disordersinclude disorders of the central nervous system, e.g., cystic fibrosis,type 1 neurofibromatosis, cognitive and neurodegenerative disorders,examples of which include, but are not limited to, Alzheimer's disease,dementias related to Alzheimer's disease (such as Pick's disease),Parkinson's and other Lewy diffuse body diseases, senile dementia,Huntington's disease, Gilles de la Tourette's syndrome, multiplesclerosis, amyotrophic lateral sclerosis, progressive supranuclearpalsy, epilepsy, and Creutzfeldt-Jakob disease; autonomic functiondisorders such as hypertension and sleep disorders, and neuropsychiatricdisorders, such as depression, schizophrenia, schizoaffective disorder,korsakoff's psychosis, mania, anxiety disorders, or phobic disorders;learning or memory disorders, e.g., amnesia or age-related memory loss,attention deficit disorder, dysthymic disorder, major depressivedisorder, mania, obsessive-compulsive disorder, psychoactive substanceuse disorders, anxiety, phobias, panic disorder, as well as bipolaraffective disorder, e.g., severe bipolar affective (mood) disorder(BP-1), and bipolar affective neurological disorders, e.g., migraine andobesity. Further cytotoxin- and metabolite-associated disorders include,for example, those listed in the American Psychiatric Association'sDiagnostic and Statistical manual of Mental Disorders (DSM), the mostcurrent version of which is incorporated herein by reference in itsentirety.

[0273] Still other examples of cytotoxin- and metabolite-associateddisorders include cellular proliferation, growth, differentiation, ormigration disorders. Cellular proliferation, growth, differentiation, ormigration disorders include those disorders that affect cellproliferation, growth, differentiation, or migration processes. As usedherein, a “cellular proliferation, growth, differentiation, or migrationprocess” is a process by which a cell increases in number, size orcontent, by which a cell develops a specialized set of characteristicswhich differ from that of other cells (e.g., spermatogenesis), or bywhich a cell moves closer to or further from a particular location orstimulus. Such disorders include cancer, e.g., carcinoma, sarcoma, orleukemia; tumor angiogenesis and metastasis; skeletal dysplasia; hepaticdisorders; and hematopoietic and/or myeloproliferative disorders.

[0274] Still other examples of cytotoxin- and metabolite-associateddisorders include disorders of the immune system, such as the immuneresponse during starvation, Wiskott-Aldrich syndrome, viral infection,autoimmune disorders or immune deficiency disorders, e.g., congenitalX-linked infantile hypogammaglobulinemia, transienthypogammaglobulinemia, common variable immunodeficiency, selective IgAdeficiency, chronic mucocutaneous candidiasis, or severe combinedimmunodeficiency. Other examples of cytotoxin- and metabolite-associateddisorders include congenital malformities, including facio-genitaldysplasia; and skin disorders, including microphthalmia with linear skindefects syndrome.

[0275] The term “family” when referring to the polypeptide and nucleicacid molecules of the invention is intended to mean two or morepolypeptides or nucleic acid molecules having a common structural domainor motif and having sufficient amino acid or nucleotide sequencehomology as defined herein. For example, the family of G2RF polypeptidescomprise at least one “transmembrane domain.” As used herein, the term“transmembrane domain” includes an amino acid sequence of about 20-45amino acid residues in length which spans the plasma membrane. Morepreferably, a transmembrane domain includes about at least 20, 25, 30,35, 40, or 45 amino acid residues and spans the plasma membrane.Transmembrane domains are rich in hydrophobic residues, and typicallyhave an alpha-helical structure. In a preferred embodiment, at least50%, 60%, 70%, 80%, 90%, 95% or more of the amino acids of atransmembrane domain are hydrophobic, e.g., leucines, isoleucines,alanines, valines, phenylalanines, prolines or methionines.Transmembrane domains are described in, for example, Zagotta W. N. etal., (1996) Annual Rev. Neurosci. 19: 235-263, the contents of which areincorporated herein by reference. Amino acid residues 129-145 of thehuman G2RF polypeptide (SEQ ID NO: 74) comprise a transmembrane domain.Accordingly, G2RF or 50566 polypeptides having at least 50-60% homology,preferably about 60-70%, more preferably about 70-80%, or about 80-90%homology with a transmembrane domain of human G2RF or 50566 are withinthe scope of the invention.

[0276] To identify the presence of a transmembrane domain in a G2RF or50566 protein, and make the determination that a protein of interest hasa particular profile, the amino acid sequence of the protein may besubjected to MEMSAT analysis. A MEMSAT analysis resulted in theidentification of a transmembrane domain in the amino acid sequence ofhuman G2RF or 50566 (SEQ ID NO: 74) at about residues 129-145.

[0277] In another embodiment, a G2RF or 50566 molecule of the presentinvention is identified based on the presence of at least one“metallo-beta-lactamase superfamily domain”, also referred tointerchangeably herein as a “lactamase-B domain.” As used herein, theterm “metallo-beta-lactamase superfamily domain” or “lactamase-B domain”includes a protein domain having an amino acid sequence of about 80-250amino acid residues and has a bit score of at least 80 when comparedagainst a metallo-beta-lactamase superfamily domain Hidden Markov Model(HMM). Preferably, a “metallo-beta-lactamase superfamily domain” has anamino acid sequence of about 90-240, 100-220, 120-200, 140-180, or morepreferably, about 165 amino acid residues, and a bit score of at least90, 100, 110, 120, or more preferably about 133.3. In a preferredembodiment, a “metallo-beta-lactamase superfamily domain” includes adomain which has an amino acid sequence of about 80-250 amino acidresidues, and serves to catalyze the hydrolysis of a thioester (e.g. thethioester in a lactoylglutathione compound). Metallo-beta lactamasesuperfamily domains are described in, for example, Carfi et al., (1995)EMBO Journal 14:4914-4921, the contents of which are incorporated hereinby reference. To identify the presence of a metallo-beta-lactamasesuperfamily domain in a G2RF protein, and make the determination that aprotein of interest has a particular profile, the amino acid sequence ofthe protein may be searched against a database of known protein domains(e.g., the HMM database). The metallo-beta-lactamase superfamily domainhas been assigned the PFAM Accession No. PF00753 and InterPro AccessionNo. IPR001279. A search was performed against the HMM database resultingin the identification of a metallo-beta-lactamase superfamily domain inthe amino acid sequence of human G2RF or 50566 (SEQ ID NO: 74) at aboutresidues 7-172 of SEQ ID NO: 74.

[0278] A description of the Pfam database can be found in Sonhammer etal. (1997) Proteins 28:405-420 and a detailed description of HMMs can befound, for example, in Gribskov et al.(1990) Meth. Enzymol. 183:146-159;Gribskov et al.(1987) Proc. Natl. Acad. Sci. USA 84:4355-4358; Krogh etal.(1994) J. Mol. Biol. 235:1501-1531; and Stultz et al.(1993) ProteinSci. 2:305-314, the contents of which are incorporated herein byreference.

[0279] In a preferred embodiment, the G2RF or 50566 molecules of theinvention include at least one transmembrane domain and/or at least onea metallo-beta-lactamase superfamily domain.

[0280] Isolated G2RF or 50566 polypeptides of the present invention,have an amino acid sequence sufficiently identical to the amino acidsequence of SEQ ID NO: 74 or are encoded by a nucleotide sequencesufficiently identical to SEQ ID NO: 73 or 75. As used herein, the term“sufficiently identical” refers to a first amino acid or nucleotidesequence which contains a sufficient or minimum number of identical orequivalent (e.g., an amino acid residue which has a similar side chain)amino acid residues or nucleotides to a second amino acid or nucleotidesequence such that the first and second amino acid or nucleotidesequences share common structural domains or motifs and/or a commonfunctional activity. For example, amino acid or nucleotide sequenceswhich share common structural domains having at least 50%, 55%, 60%,65%, 70%, 75%, 80%, 85%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or morehomology or identity across the amino acid sequences of the domains andcontain at least one and preferably two structural domains or motifs,are defined herein as sufficiently identical. Furthermore, amino acid ornucleotide sequences which share at least 50%, 52%, 53%, 54%, 55%, 60%,65%, 70%, 75%, 80%, 85%, 85%, 90%, 95%, 96%, 97%, 98%,-99% or morehomology or identity and share a common functional activity are definedherein as sufficiently identical.

[0281] In a preferred embodiment, a G2RF or 50566 polypeptide includesat least one or more of the following domains: a transmembrane domainand/or a metallo-beta-lactamase superfamily domain, and has an aminoacid sequence at least about 50%, 53%, 54%, 55%, 60%, 65%, 70%, 75%,80%, 85%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more homologous oridentical to the amino acid sequence of SEQ ID NO: 74. In yet anotherpreferred embodiment, a G2RF polypeptide includes at least one or moreof the following domains: a transmembrane domain and/or ametallo-beta-lactamase superfamily domain, and is encoded by a nucleicacid molecule having a nucleotide sequence which hybridizes understringent hybridization conditions to a complement of a nucleic acidmolecule comprising the nucleotide sequence of SEQ ID NO: 73 or SEQ IDNO: 75. In another preferred embodiment, a G2RF polypeptide includes atleast one or more of the following domains: a transmembrane domainand/or a metallo-beta-lactamase superfamily domain, and has a G2RFactivity.

[0282] As used interchangeably herein, “G2RF or 50566 activity”,“biological activity of G2RF or 50566” or “functional activity of G2RFor 50566”, includes an activity exerted by a G2RF polypeptide or nucleicacid molecule on a G2RF responsive cell or tissue, or on a G2RFpolypeptide substrate, as determined in vivo, or in vitro, according tostandard techniques. In one embodiment, a G2RF activity is a directactivity, such as an association with a G2RF-target molecule. As usedherein, a “target molecule” or “binding partner” is a molecule withwhich a G2RF polypeptide binds or interacts in nature, such thatG2RF-mediated function is achieved. A G2RF target molecule can be anon-G2RF molecule, for example, a non-G2RF polypeptide. In an exemplaryembodiment, a G2RF target molecule is a G2RF ligand, e.g., a cytotoxin,a metabolite, glutathione, a gluathione-conjugated compound such aslactoylglutathione, or a thioester-containing compound. For example, aG2RF target molecule can have one or more of the following activities:(1) it may interact with cytotoxins and metabolites (e.g.,lactoylglutathione, a glutathione-conjugated metabolite, ahydroxycarboxylic acid, and the like), (2) it may catalyze themebobolism of a cytotoxin or metabolite (e.g., lactoylglutathione, aglutathione-conjugated metabolite, a hydroxycarboxylic acid, and thelike), (3) it may hydrolyze a thioester containing compound (e.g.,lactoylglutathione, and the like), (4) it may catalyze the formation ofa thioester conjugation on a substrate (e.g., lactate or ahydroxycarboxylic acid). Moreover, a G2RF activity is an indirectactivity, such as a cellular signaling activity mediated by interactionof the G2RF polypeptide with a G2RF ligand. The biological activities ofG2RF are described herein. For example, the G2RF polypeptides of thepresent invention can have one or more of the following activities: (1)modulation of signal transduction in a cell, (2) modulation of cytotoxinand/or metabolite levels (e.g., detoxification), (3) maintenance ofequilibrium of cytotoxins and/or metabolites, (4) modulation of canceror tumor progression, (5) modulation of cellular proliferation, (6)modulation of tissue development (e.g. embryogenesis), (7) modulation ofdifferentiation, (8) modulation of apoptosis, and (9) modulation ofenergy metabolism.

[0283] The human G2RF or 50566 cDNA sequence (SEQ ID NO: 73), which isapproximately 1154 nucleotide residues long including un-translatedregions, contains a predicted methionine-initiated coding sequence ofabout 846 nucleotide residues, (nucleotide residues 22-867 of SEQ ID NO:73; 1-846 SEQ ID NO: 75), not including the terminal codon. The codingsequence encodes a 282 amino acid protein having the amino acid sequenceSEQ ID NO: 74.

[0284] Analysis of the Human G2RF or 50566 Molecules

[0285] A search using the polypeptide sequence of SEQ ID NO: 74 wasperformed against the HMM database in PFAM resulting in theidentification of a metallo-beta-lactamase superfamily domain in theamino acid sequence of human G2RF or 50566 at about residues 7-172 ofSEQ ID NO: 74 (score=133.3).

[0286] A search using the polypeptide sequence of SEQ ID NO: 74 was alsoperformed against the Memsat database, resulting in the identificationof a potential transmembrane domain in the amino acid sequence of humanG2RF or 50566 (SEQ ID NO: 74) at about residues 129-145, and theidentification of a potential signal peptide in the amino acid sequenceof human G2RF at about residues 1-54 of SEQ ID NO: 74.

[0287] Further domain motifs were identified by using the amino acidsequence of 50566 (SEQ ID NO: 74) to search the ProDom database.Numerous matches against protein domains described as “Hydrolase IIHydroxyacylglutathione Glyoxalase Glx Zinc Cytoplasmic Plasmid PeptideMultigene”, Hydrolase Similar Flavoprotein Rv2260 TuberculosisMycobacterium PH1213”, “Hydrolase II Hydroxyacylglutathione ZincGlyoxalase Glx Precursor Family”, “II Hydrolase Glyoxalase GlxHydroxyacylglutathione Zinc Precursor Specific MNCB-5687 Peptide” andthe like were identified.

[0288] A search was also performed against the Prosite database, whichresulted in the identification of a potential “cAMP- and cGMP-dependentprotein kinase phosphorylation site” at residues 232-235 of SEQ ID NO:74 (Prosite accession number PS00004), two potential “Protein kinase Cphosphorylation sites” at residues 86-88 and 235-237 of SEQ ID NO: 74(Prosite accession number PS00005), multiple potential “Casein kinase IIphosphorylation sites” at residues 143-146, 155-158, 177-180 and 213-216of SEQ ID NO: 74 (Prosite accession number PS00006), and multiplepotential N-myristoylation sites at residues 44-49, 140-145 and 274-279of SEQ ID NO: 74 (Prosite accession number PS00008).

[0289] The amino acid sequence of human G2RF or 50566 was analyzed usingthe program PSORT to predict the localization of the proteins within thecell. This program assesses the presence of different targeting andlocalization amino acid sequences within the query sequence. The resultsof the analyses show that human G2RF may be localized to the cytoplasm,nucleus, mitochondria, or golgi.

[0290] Tissue Expression Analysis of G2RF mRNA Using Taqman Analysis

[0291] The following describes the tissue distribution of human G2RFmRNA in a variety of cells and tissues, as determined using the TaqMan™procedure.

[0292] An array of human tissues were tested. Expression was greatest inthe brain cortex and hypothalamus, normal skin, heart with coronaryheart failure (CHF) and erythroid cells. Expression was also high in thekidney, coronary smooth muscle cells (SMC), human umbilical veinepithelial cells (HUVEC), normal spinal cord tissue, dorsal rootganglions and colon tumor.

[0293] Human 65552

[0294] The present invention is based, in part, on the discovery of anovel gene encoding an MMP (“MMP” is used interchangeably herein with“matrix metalloprotease”, “matrix metalloprotease-ADAMTS” and “matrixmetalloproteinase”), the gene referred to herein as “65552”.

[0295] The human 65552 cDNA sequence (SEQ ID NO: 76), which isapproximately 2853 nucleotide residues long including un-translatedregions, contains a predicted methionine-initiated coding sequence ofabout 2850 nucleotide residues, (i.e., nucleotide residues 1-2850 of SEQID NO: 76; also shown in SEQ ID NO: 78). The coding sequence encodes a950 amino acid protein having the amino acid sequence SEQ ID NO: 77.

[0296] A hydropathy plot of human 65552 was performed. Polypeptides ofthe invention include fragments which include: all or part of ahydrophobic sequence, e.g., the sequence from about amino acid 408 to424 of SEQ ID NO: 77; a sequence which includes a Cys, or aglycosylation site.

[0297] The 65552 protein contains a significant number of structuralcharacteristics in common with members of the matrix metalloproteinase(MMP) family. The 65552 protein contains a significant number ofstructural characteristics in common with members of the adamalysins(reprolysin) family. For example, the 65552 molecule may contain apeptidase M12B propeptide domain, a reprolysin domain, and athrombospondin domain.

[0298] Matrix metalloproteinase adamalysin molecules require a metal forcatalyzing the cleavage of peptides or proteins. Typically, theseproteases require zinc for the catalysis, ligands for which can behistidine residues. Many of these proteins have collagenase-likecatalytic activity. For example, collagens are extracellular matrixproteins responsible for the architecture and structural integrity ofmost tissues and stromelysin, which degrade the extracellular matrix.

[0299] Metalloproteases (also referred to herein as “metallopeptidases”or “metalloproteinases” or “MMPs”) are a group of highly diverse, widelydistributed proteolytic enzymes that depend on bound Ca²⁺ or Zn²⁺ foractivity. Certain metalloproteases can readily utilize Mn²⁺ and Mg²⁺ aswell. About 30 families of metalloproteases are recognized, about halfof which comprise enzymes containing the HEXXH motif (SEQ ID NO: 84)(Rawlings et al. (1995) Meth Enzymol 248:183-228). The most thoroughlycharacterized of the metalloproteases is thermolysin, a member of the M4metalloprotease family.

[0300] Another metalloprotease family, the M12 family, contains thereprolysin (M12B) subfamily, which contains the snake venommetalloproteases and adamalysins family. The reprolysin subfamily alsoincludes BRCA1, a human breast cancer-associated protein, and mammalianfertilin.

[0301] The ADAM subfamily of reprolysins comprises a broad family ofmultifunctional proteins, members of which may include, but are notlimited to, a disintegrin and/or a metalloprotease domain (Wolfsberg etal. (1995) Developmental Biol 169:378-383; Wolfsberg et al. (1995) JCell Biol 131:275-278; Hurskainen et al. (1999) J Biol Chem274:25555-25563).

[0302] The ADAMs are expressed by a wide variety of cell types, and areinvolved in functions as diverse as sperm-egg binding, myotubeformation, neurogenesis, and proteolytic processing of cell surfaceproteins. Their functions involve proteolysis on the cell surface: theformation and inactivation of regulatory peptides and growth factors, aswell as modification of cell surface proteins. Most members of thisfamily are snake venom endopeptidases, but there are also some mammalianproteins such as fertilin and TACE. (Fertilin is involved in sperm-eggbinding, and TACE is a member of the ADAM family that cleavesmembrane-bound TNF-alpha to generate soluble TNF-alpha). The activeenzymes degrade components of the extracellular matrix, playing a rolein the initial steps of tissue remodeling during morphogenesis, woundhealing, angiogenesis and tumor invasion.

[0303] The ADAMTSs (“a disintegrin and metalloprotease withthrombosponding type I motifs”) subfamily of ADAMs are similar in domainorganization (though different from other ADAM family members), havingone or more of the following domains: a signal peptide, peptidase M12Bpropeptide domain, a zinc binding region signature a domain, acysteine-rich domain, a thrombospondin type-1 domain, and in many casesa membrane-spanning region and a cytoplasmic domain with signalingpotential. For example, ADAMTS-1 differs from other ADAM family membersdue to a lack of the cysteine rich, EGF and transmembrane domains andthe addition of thrombospondin type I motifs (Kuno et al. (1997) J BiolChem 272: 556-562).

[0304] Reprolysin (M12B) is a zinc metalloprotease family member with nodisintegrin-like domain, but with one propeptide for members of thepeptidase family M12, and one thrombospondin type I motif. Theseproteins have collagenase-like catalytic activity. For example,collagens are extracellular matrix proteins responsible for thearchitecture and structural integrity of most tissues. They aresynthesized as procollagens and go through a series ofpost-translational modifications both inside and outside the cell beforethey are fully functional (Duance and Bailey (1981) Handbook ofInflammation. Vol. 3 Tissue Regeneration and Repair, ed. Glynn, L EElsevier, Amsterdam, 51-109). Included in collagen maturation are thesteps of removing the extension peptides from the N- and C-termini. Thefailure of this process results in many connective tissue disorders, forexample, Ehlers-Danlos syndrome type VIIC, characterized by theretention of the N-terminal propeptide of collagen I (Lenaers et al.(1971) Eur J Biochem 23: 533-543) by a metalloprotease, procollagen IN-protease (Colige et al. (1999) Am. J. Hum. Genet. 65: 308-317).

[0305] The known members of the reprolysin subfamily mostly lackessential peptidase active sites, but can contain one of the followingdomains: a C-terminal disintegrin-like domain, an epidermal growthfactor (EGF)-like domain, and transmembrane domains (Rawlings et al.(1995) Meth Enzymol 248:183-228). In addition, members of the reprolysin(M12B) subfamily of zinc metalloproteases contain a reprolysinpropeptide region. Many MMPs are expressed as latent pro-enzymes thatare activated by proteolytic cleavage. Cleavage of the M12B propeptidetriggers a conformational change in the propeptide, thereby convertingan M12B family type metalloprotease to its active strate. Coordinationof Zn2+ in the active site of the catalytic domain of the M12Bpropeptide by a cysteine residue in the prodomain is critical forinhibition of the protease. (Overgaard et.al. (1999), J Biol. Chem,7:274(19):13427-33).

[0306] The reprolysin domain is characteristic of extracellularmetalloproteinases, such as collagenase and stromelysin, which degradethe extracellular matrix. The members of this family are enzymes thatcleave peptides. These proteases require zinc for catalysis, ligands forwhich can be histidine residues. Members of this family are also knownas adamalysins. There are two subfamilies of adamalysins: the snakevenom metalloproteases (SVMPs) and the ADAMs (“a disintegrin andmetalloprotease”). At least 23 ADAMs have been identified to date.Members of the ADAMs family of proteins include, but are not limited to,MDC (ADAM 1), ADAMTS-1, fertilin (ADAM2), cryitestin (ADAM3), epididymalapical protein I, meltrin, MS2, TNF-a converting enzyme, Kuzbanian andmetargidin.

[0307] The thrombospondin type I (TSP I) motifs in ADAMTS-1 enable it tobind to the extracellular matrix (Kuno and Matsushima (1998) J Biol Chem273: 13912-13917). TSP I motifs are conserved domains in thrombospondin1 and 2, multifunctional secretory glycoproteins involved in bloodclotting, inhibiting angiogenesis and regulating the proliferation,adhesion and migration of normal and tumor cells. The biologicalactivities of thrombospondin 1 and 2 are mediated by the binding of theTSP type I motifs to extracellular matrix molecules, such as heparansulfate, proteoglycans, fibronectin, laminin and collagen.Thrombospondin-1 is a platelet-derived glycoprotein that is releasedfrom platelet alpha granules in response to thrombin stimulation. It isinvolved in cell adhesion and modulates cell movement, cellproliferation, neurite outgrowth and angiogenesis. In general, thebiological functions of metalloproteases include protein maturation,degradation of proteins, such as extracellular matrix proteins (ECMproteins), tumor growth, metastasis and angiogenesis, among others.Thus, metalloproteases are likely to play important roles in a widerange of diseases including, but not limited to, cancer, arthritis,Alzheimer's disease, and a variety of inflammatory conditions. Othernormal and pathological processes in which MMP-catalyzed changes in ECMprotein structures have been implicated are described, for example, inNagase et al. (1999) J. Biol. Chem. 274:21491-21494. Accordingly,metalloproteases are an important target for drug action anddevelopment. Therefore, it is valuable to the field of pharmaceuticaldevelopment to identify and characterize previously unknownmetalloproteases.

[0308] A human 65552 polypeptide can include a reprolysin domain.

[0309] In a preferred embodiment, the reprolysin domain ischaracteristic of extracellular metalloproteinases.

[0310] As used herein, the term “reprolysin domain” refers to a proteindomain having an amino acid sequence of about 100-300 amino acidresidues in length, and having an E value of about 2.5e-8. Preferably,the reprolysin domain has a length of about 100-300 amino acid residuesin length, preferably about 150-250 amino acid residues in length, morepreferably about 175-225 amino acid residues in length, and even morepreferably about 205-220 amino acids residues in length, and has anE-value of about 2.5 e-9 or less, more preferably about 2.5 e-10 orless, and most preferably about 2.5e-11 or less. The reprolysin domainhas been assigned the PFAM Accession number PF01421.

[0311] The consensus sequence for a reprolysin domain was derived from ahidden Markov model (HMM) within Pfam (version 5.5) (PFAM Accessionnumber PF01421). An alignment of the 65552 protein with a consensusreprolysin amino acid sequence (SEQ ID NO: 80) has a predicted bit scoreof 9.3, and an E-value of 2.5e-1 1. Preferably, the reprolysin domainhas the ability to cleave a protein or peptide in the presence of ametal (i.e., Zn⁺⁺).

[0312] A reprolysin domain of a 65552 protein can also include a neutralzinc metallopeptidases, zinc-binding region having the followingsignature sequence:[GSTALIVN]-x(2)-H-E-[LIVMFYW]-{DEHRKP}-H-x-[LIVMFYWGSPQ] (SEQ ID NO:83). In this signature sequence pattern, each element in the pattern isseparated by a dash (-); square [] brackets indicate the particularresidues that are accepted at that position; elaborate {} bracketsindicate the residues that are not accepted at that position; xindicates any residue is accepted at that position; a whole number inparenthesis following an x indicates any amino acid repetition of aparticular element is accepted for that specified number of residuesi.e., x(4), and the standard IUPAC one-letter code for the amino acidsis used. The two H's are zinc ligands and E is the active site residue.

[0313] This signature sequence can be found from about residues 358 to367 of the 65552 protein (SEQ ID NO: 77). For example, the conservedhistidines can be found at about amino acid residues 361 and 365 of SEQID NO: 77. These histidine residues are believed to interact with zincions.

[0314] In a preferred embodiment, 65552 polypeptide or protein has areprolysin domain or a region which includes at least about 100 to 300,more preferably about 150 to 250, 175 to 225, 205 to 220 amino acidresidues and has at least about 60%, 70%, 80%, 90%, 95%, 99%, or 100%identity with a reprolysin domain, e.g., the domain of human 65552(e.g., residues 218 to 427 of SEQ ID NO: 77) (SEQ ID NO: 80). Preferablya 65552 polypeptide or protein contains the typical neutral zincmetallopeptidases, zinc binding region signature sequence describedabove. This sequence is located at about amino acid residues 357 to 367of SEQ ID NO: 77.

[0315] A 65552 polypeptide can also include one or more peptidase M12Bpropeptide domains. As used herein, the term “peptidase M12B propeptidedomain” refers to a protein domain having an amino acid sequence ofabout 40 to 160 amino acid residues in length, and having an E value ofabout 4.3 e-3. The peptidase M12B propeptide domain has a length ofabout 40 to 160 amino acid residues, preferably between about 60 to 150amino acids residues in length, more preferably between about 80 to 130amino acid residues in length, and even more preferably between about100 to 120 amino acid residues in length, and has an E-value of about4.3e-4 or less, more preferably 4.3-5 or less, and most preferably about4.3e-6 or less.

[0316] The peptidase M12B propeptide domain of the 65552 polypeptideshows homology to the peptidase M12B propeptide domain corresponding toPFAM Accession PF06562 derived from a hidden Markov model (HMM) withinPfam (version 5.5) (PFAM Accession number PF01562) (SEQ ID NO: 79). Analignment of the 65552 protein (residues 67-181 of SEQ ID NO: 77) with aconsensus peptidase M12B propeptide amino acid sequence derived from ahidden Markov model as predicted by PFAM has a bit score of 25.7, and anE-value of 24.3e-6.

[0317] In a preferred embodiment, a 65552 polypeptide or protein has apeptidase M12B propeptide domain or a region which includes at leastabout 40-160 amino acids, preferably about 60-150 amino acids, morepreferably about 80-130 amino acids, even more preferably about 100-120amino acid residues and has at least about 60%, 70%, 80%, 90%, 95%,99%,or 100% identity with a peptidase M12B propeptide domain (e.g., thepeptidase M12B propeptide domains of human 65552 (e.g., residues 67-181of SEQ ID NO: 77).

[0318] The peptidase M12B propeptide domain may be involved inmaintaining the protease in a latent form. The propeptide contains asequence motif similar to the “cysteine switch” of matrixins. Thefunction of the domain can be explained by the cysteine switch model, inwhich coordination of Zn2+ in the active site of the catalytic domain bya cysteine residue in the prodomain is critical for inhibition of theprotease.

[0319] A 65552 polypeptide can also include one or more thrombospondintype 1 domains. As used herein, the term “thrombospondin type 1 domain”also referred to herein as “TSP-1 domain” refers to a protein domainhaving an amino acid sequence of about 10 to 100 amino acid residues inlength, and an E value of about 1.5e-4. Preferably, the TSP-1 domain isbetween 10 to 100 amino acid residues in length, preferably betweenabout 20 to 80 amino acids residues in length, more preferably betweenabout 40 to 60 amino acid residues in length, and even more preferablybetween about 45 to 55 amino acids in length, and has an E-value ofabout 1.5e-5 or less, more preferably about 1.5e-5 or less, and mostpreferably about 1.5e-7 or less. The thrombospondin type 1 domain hasbeen assigned the PFAM Accession number PF00090. An alignment of the65552 protein, (amino acid residues 520-570 of SEQ ID NO: 77) with aconsensus thrombospondin type 1 amino acid sequence (SEQ ID NO: 81)derived from a hidden Markov model within Pfam (version 5.5) (PFAMAccession number PF00090) (SEQ ID NO: 81) has a bit score of 38.5, andan E-value of 1.5e-07.

[0320] In a preferred embodiment, a 65552 polypeptide or protein has athrombospondin type 1 domain or a region which includes at least about10-100 amino acids, preferably about 20-80 amino acids, more preferablyabout 40-60 amino acids, even more preferably about 45-55 amino acidresidues and has at least about 60%, 70%, 80%, 90%, 95%, 99%, or 100%identity with a thrombospondin type 1 domain, e.g., the thrombospondintype 1 domains of human 65552 (e.g., 520-570 of SEQ ID NO: 77).

[0321] Preferably, the thrombospondin type 1 domain has the ability tosuppress tumor growth by its ability to inhibit neovascularization(angiogenesis) and proliferation. Preferably as well, the thrombospondintype 1 domain has the ability to modulate cell-cell interaction (i.e.,modulating endothelial cell growth, adhesion, and motility andapoptosis).

[0322] To identify the presence of a reprolysin domain profile, apeptidase M12B propeptide domain profile, and a thrombospondin type 1domain profile in a 65552 polypeptide, the amino acid sequence of theprotein is searched against a database of HMMs (e.g., the Pfam database,release 2.1) using the default parameters. For example, the hmmsfprogram, which is available as part of the HMMER package of searchprograms, is a family specific default program for PF01421, PF01562, andPF00090 and score of 15 is the default threshold score for determining ahit. Using the hmmsf program, the following domains were identified: areprolysin domain profile was identified in the amino acid sequence ofSEQ ID NO: 77 (e.g., amino acids 218-427 of SEQ ID NO: 77 (SEQ ID NO:80)); a peptidase M12B propeptide was identified in the amino acidsequence of SEQ ID NO: 77 (e.g., amino acids 67-181 of SEQ ID NO: 77(SEQ ID NO: 79)), and a thrombospondin type 1 domain profile wasidentified in the amino acid sequence of SEQ ID NO: 77 (e.g., aminoacids 520-570 of SEQ ID NO: 77 (SEQ ID NO: 81)). Accordingly, a 65552protein, or a domain thereof having at least about 60-70%, morepreferably about 70-80%, or still more preferably about 80-90% homologywith the reprolysin domain profile, and the peptidase M12B propeptidedomain profile, and the thrombospondin type 1 domain profile of human65552 are within the scope of the invention.

[0323] For further identification of polyptides, and demonstration ofshared characteristics with other metalloproteases, the 65552polypeptide molecule is aligned to that of other metaloproteases. Analignment of human 65552 protein (SEQ ID NO: 77) with a murinemetalloproteinase (Swissprot Accession #: 054768: SEQ ID NO: 82)demonstrates that these sequences are 43.4% identical, and have a glogalalignment score of 2516.

[0324] The human 65552 polypeptide can also contains a leucine zipperpattern, or regions homologous with a leucine zipper pattern.

[0325] Metalloproteases, fragments or variants thereof can have aleucine zipper motif or regions homologous with a leucine zipper motif.Leucine zippers typically contain a repeat of leucine positioned everyseven amino acids (L-x(6)-L-x(6)-L-x(6)-L) (SEQ ID NO: 85), over adistance of eight helical turns. The segments containing these periodicarrays of leucines appear to exist in an alpha-helical conformation inwhich leucine side chains extending from one alpha-helix interact withthose from a similar alpha helix of a second polypeptide, facilitatingdimerization. These interactions are frequently required for theactivity of the protein complex, e g., transcriptional activation of anucleic acid via binding to a gene regulatory sequence and subsequentformation of a transcription initiation complex. Leucine zipperstherefore mediate protein-protein interactions in vivo and inparticular, interactions between multi-subunit transcription factors(homodimers, heterodimers, etc.).

[0326] Thus, in another embodiment, a 65552 metalloprotease or fragmentor variant can have one or more activities of a leucine zipper motif,such as binding to another polypeptide that has a leucine zipper, forexample, forming a dimer with a 65552 metalloprotease or fragment orvariant containing a leucine zipper. The presence of a leucine zippermotif indicates that 65552 metalloprotease can participate in differentpathways due to an ability to interact with different proteins via theleucine zipper motif. For example, the leucine zipper motif can allow65552 metalloprotease binding to a protein substrate which 65552 maythen cleave. Thus, the leucine zipper motif modulates or is involved inone or more activities or functions of 65552 metalloprotease through itsability to confer binding of 65552 metalloprotease to a target moleculeor binding partner. The term “leucine zipper activity,” when used inreference to a protein, means a protein having one or more activitiesassociated with leucine-zipper function as described herein or otherwiseknown in the art.

[0327] 65552 proteins of the invention can have signal sequences. Asused herein, a “signal sequence” includes a peptide of at least about 15or 20 amino acid residues in length which occurs at the N-terminus ofsecretory and membrane-bound proteins and which contains at least about70% hydrophobic amino acid residues such as alanine, leucine,isoleucine, phenylalanine, proline, tyrosine, tryptophan, or valine. Ina preferred embodiment, a signal sequence contains at least about 10 to40 amino acid residues, preferably about 15-30 amino acid residues, morepreferably about 17 amino acid residues, and has at least about 60-80%,more preferably 65-75%, and more preferably at least about 70%hydrophobic residues. A signal sequence serves to direct a proteincontaining such a sequence to a lipid bilayer. Thus, in one embodiment,a 65552 protein contains a signal sequence at about amino acids 1 to 17of SEQ ID NO: 77. The signal sequence is cleaved during processing ofthe mature protein.

[0328] In one embodiment, a 65552 protein exists in a mature form whichdoes not include a signal sequence. In this embodiment, the 65552protein can have a length of about 934 (e.g., 927, 928, 929, 930, 931,932, 933, 934, 935, 936, or 937) amino acid residues, corresponding to aprotein having an amino terminus at about residue 18 (e.g., at residues15, 16, 17, 18, 19 or 20) and having a carboxyl terminus at aboutresidue 950 of SEQ ID NO: 77. In this embodiment, the protein ispreferably not membrane-bound, and is also preferably extracellular.

[0329] The human 65552 protein has four predicted N-glycosylation sites(Pfam Accession number PS00001) at about amino acid residues 141-144,591-594, 623-626 and 679-682 of SEQ ID NO: 77; two glycosaminoglycanattachment sites (PFAM Accession Number PS00002) at about amino acidresidues 417-420 and 760-763; two cAMP and cGMP-dependent protein kinasephosphorylation sites (PFAM Accession Number PS00004) at about aminoacid residues 204-207 and 683-686 of SEQ ID NO: 77; fourteen predictedprotein kinase C phosphorylation sites (PFAM Accession Number PS00005)at about amino acid residues 171-173, 203-205, 207-209, 288-290,303-305, 471-473, 575-577, 578-580, 594-596, 617-619, 611-613, 665-667,681-683, and 917-919 of SEQ ID NO: 77; fourteen predicted casein kinaseII phosphorylation sites (PFAM Accession Number PS00006) located atabout amino acid residues 19-22, 317-320, 325-328, 337-340, 346-349,359-362, 432-435, 492-495, 578-581, 611-614, 707-710, 730-733, 744-747,and 764-767 SEQ ID NO: 77; fifteen predicted N-myristoylation sites(PFAM Accession Number PS00008) at about amino acid residues 90-95,105-110, 121-126, 164-169, 175-180, 323-328, 352-357, 439-444, 476-481,490-495, 535-540, 551-556, 658-663, 673-678, and 761-766 of SEQ ID NO:77; one predicted amidation site (PFAM Accession Number PS00009) atabout amino acid residues 36-39 of SEQ ID NO: 77; one predicted leucinezipper pattern (PFAM Accession Number PS00029) at about amino acidresidues 238-259 of SEQ ID NO: 77; one zinc binding signature (PFAMAccession Number PS00142) at about amino acid residues 358-367 of SEQ IDNO: 77; and one P-II protein urydylation site at about amino acidresidues 129-134 of SEQ ID NO: 77.

[0330] Information regarding PFAM identifiers, PS prefix and PF prefixdomain identification numbers can be found at Sonnhammer et al. (1997)Protein 28:405-420.

[0331] In one embodiment of the invention, a 65552 polypeptide includesat least one reprolysin domain. In another embodiment, the 65552polypeptide comprises at least one reprolysin domain and at least onepeptidase M12B propeptide domain. In still another embodiment, the 65552polypeptide contains at least one reprolysin domain, at least onepeptidase M12B propeptide domain, and at least one thrombospondin type-1domain.

[0332] The 65552 molecules of the present invention can further includeone or more of the N-glycosylation,glycosaminoglycan attachment, cAMPand cGMP-dependent protein kinase phosphorylation, protein kinase Cphosphorylation, casein kinase II phosphorylation, N-myristoylation,amidation, leucine zipper, zinc binding signature, and P-II proteinurydylation sites sites described herein.

[0333] Because the 65552 polypeptides of the invention can modulate65552-mediated activities, they can be used to develop novel diagnosticand therapeutic agents for 65552-mediated or related disorders, asdescribed herein.

[0334] As used herein, a “65552 activity,” “biological activity of65552,” or “functional activity of 65552,” refers to an activity exerted(directly or indirectly) by a 65552 protein, polypeptide or nucleic acidmolecule on, for example, a 65552-responsive cell or on a 65552substrate (e.g., a protein substrate) as determined in vivo or in vitro.In one embodiment, a 65552 activity is a direct activity, such asassociation with a 65552 target molecule. A “target molecule” or“binding partner” of a 65552 protein is a molecule with which the 65552protein binds or interacts in nature. In an exemplary embodiment, such atarget molecule is a 65552 receptor. A 65552 activity can also be anindirect activity, such as a cellular signaling activity mediated byinteraction of the 65552 protein with a 65552 receptor.

[0335] The 65552 molecules of the present invention can have similarbiological activities as other MMP family members. For example, the65552 proteins of the present invention can modulate (directly orindirectly) any one or more of the following activities: 1) smoothmuscle cell function (i.e., the muscular component of visceralstructures (i.e., blood vessels, the gastrointestinal tract, the uterus,or the urinary bladder)); 2) function of muscular arterial cells.(i.e.,cells of radial arteries, (i.e., cells of the tunica intima or thetunica adventicia; 3) catalyzed cleavage of covalent bonds within orbetween amino acid residues in, for example, ECM, cell-surface, andextracellular proteins; 4) degradation of ECM; 5) angiogenesis; 6)neurite growth; 7 tumor cell invasion or metastasis; 8) the ability tomodulate tissue or organ integrity; 9) wound healing; 10) endometrialcycling; 11) hair follicle cycling; 12) bone remodeling; 13) ovulation;14 embryonic development; or 15) apoptosis.

[0336] Other activities, as described herein, include the ability tomodulate function, survival, morphology, proliferation and/ordifferentiation of cells of tissues in which 65552 molecules areexpressed. Thus, the 65552 molecules can act as novel diagnostic targetsand therapeutic agents for controlling disorders involving aberrantactivities of these cells.

[0337] As used herein, the term “metalloprotease activity,” or “proteaseactivity” when used in reference to a protein, means a protein havingthe ability to cleave a protein substrate by hydrolysis of an amidebond. Typically, the ability to cleave a protein substrate depends uponthe presence of a metal ion, such as zinc. Thus, a 65552metalloproteinase or fragment or variant having metalloproteinaseactivity is capable of cleaving one or more protein substrates in thepresence of a metal, e.g., zinc. Thus, a 65552 metalloproteinase orfragment or variant having metalloproteinase activity is capable ofcleaving one or more protein substrates in the presence of zinc.

[0338] Activity assays for the metalloproteinase family members, such as65552 polypeptides, involve any of the known metalloproteinase,reprolysin, or thrombospondin-like activity or functions, as well asactivities/functions that may not typically be found in othermetalloproteinases. These assays include, but are not limited to: 1)binding extracellular matrix; 2) binding collagen or gelatin; 3) bindingintegrin; 4) binding zinc or other metals; 5) binding a2-macroglobulin;6) cleaving specific peptide substrates to produce fragments, affectingcell adhesion; 7) binding heparin or other sulfated glycosaminoglycan,such as heparan sulfate; 8) modulation of vascularization or vascularendothelial growth; 9) breaking down cartilage; 10) induction ofapoptosis of endothelial cells; 11)suppressing tumor growth; 12)modulating angiogenesis; 13) affecting cellular chemotaxis; 14)affecting cell-cell adhesion or cell-matrix interaction; 15) bindingintegrin; 16) and any of the other biological or functional propertiesof these proteins, including, but not limited to, those disclosedherein, and in the references cited herein. Further, assays can relateto changes in the protein, per se, and on the effects of these changes,for example, cleavage of the substrate, activation of the proteinfollowing cleavage, etc. Such assays are described in Tang et al. (1999)FEBS Letters 445:223-225 (for example, induction by interleukin I invitro and by intravenous administration of lipopolysaccharide in vivo,as well as effects on cell adhesion, motility, and growth); Abbaszade etal., (J Biol Chem. August 2000 18;275(33):25791-7). (for example,products resulting from cleavage at the Glu-Ala site in cartilageexplants and chondrocyte cultures treated with interleukin I andretinoic acid, determination of aggrecan cleaving activity with andwithout hydroxamate inhibitors); (Kuno and Matsushima (1998) J Biol Chem273: 13912-13917) (binding to the extracellular matrix, binding tosulfated glycosaminoglycans, binding to heparan sulfate); Kuno et al. J(1999) Biol Chem. June 25;274(26):18821-6. (protease trapping ofa2-macroglobulin, furin processing); Tortorella et al.(1999) Science.284(5420): 1664-6. (detection of aggrecan fragments, especially byneoepitope antibodies, inhibition of cleavage by ADAM-TS inhibitors,inhibition of pro-MMP activation); Vasquez et al., J Appl Physiol.(1998) October;85(4):1421-8. (suppression of fibroblast growthfactor-2-induced vascularization in the cornea pocket assay andinhibition of vascular endothelial growth factor-induced angiogenesis inthe chorioallantoic membrane assay, inhibition of endothelial cellproliferation, competitive inhibition with endostatin, proliferation ofhuman dermal endothelial cells, use of the antiangiogenic region of theTSP-1 motif as bait); (Kuno et al. (1997) J Biol Chem 272: 556-562).;Wolfsberg et al., Dev Biol. May 1995;169(l):378-83.; Guilpin et al.(1988) J. Biol. Chem. 273:157-166 (α2-macroglobulin trapping, cleavageof prodomain at the furin site to generate active metalloproteinase);Rosendahl et al., (1997)(J. Biol. Chem. 272:24588-24593)) (TNF αprocessing). Recombinant assay systems include, but are not limited to,those described in Abbaszade et al., supra; Kuno et al. (1998), supra;Kuno et al. (1999), supra; Tortorella et al., supra; Vasquez et al.,supra, and Kuno et al. (1997), supra.

[0339] As used herein, the term “TSP activity” or “TSP function,” whenused in reference to a protein, means a protein that has one or moreactivities associated with a TSP e.g., a TSP-1 domain as describedherein or otherwise known in the art. For example, TSP domains areinvolved in cell adhesion, migration, proliferation, outgrowth orangiogenesis. Thus, a 65552 metalloproteinase or fragment or varianthaving a TSP activity can mediate or modulate cell-cell adhesion (e.g.,due to the presence of 65552 metalloproteinase in extracellular matrix),motility/migration, proliferation, outgrowth or angiogenesis, forexample. TSP domains also have been implicated in inflammatoryconditions and, therefore, a 65552 metalloproteinase or fragment orvariant with a TSP domain can participate in a pathway that affects aninflammatory response.

[0340] The 65552 metalloproteinase molecules find use in modulating65552 metalloproteinase function, activity, or expression, or relatedresponses to metalloproteinase function, activity or expression. As usedherein, the term “modulate” or grammatical variations thereof meansincreasing or decreasing an activity, function, signal or response. Thatis, the 65552 metalloproteinase molecules of the invention affect thetargeted activity in either a positive or negative fashion (e.g.,increase or decrease activity, function, or signal). Accordingly, the65552 molecules can act as novel diagnostic targets and therapeuticagents for controlling metalloproteinase disorders.

[0341] Thus, 65552 molecules described herein can act as noveldiagnostic targets and therapeutic agents for prognosticating,modulating, diagnosing, preventing, inhibiting, alleviating, or treatingmetalloproteinase-associated disorders.

[0342] As used herein, a “metalloproteinase-associated disorder”(MMP-associated disorder) includes a disorder, disease or conditionwhich is characterized by a misregulation of a metalloproteinasemediated activity or by an abnormal metalloproteinase mediated activity.Metalloproteinase-associated disorders can detrimentally affect cellproliferation, cell adhesion, cell motility and migration, tissuestructural integrity (e.g., connective tissue formation andmaintenance), inflammatory response, erythroid cell activity, geneexpression; or angiogenesis and vascularization, among others. Thus,examples of metalloproteinase associated disorders in which the 65552molecules of the invention can be directly or indirectly involvedinclude cellular proliferative and/or differentiative disorders;disorders associated with undesirable or deficientvascularization/angiogenesis; disorders associated with undesirable ordeficient cell adhesion, motility or migration, including, e.g.,metastasis; disorders associated with undesirable or deficient tissuestructural integrity; disorders associated with undesirableextracellular matrix accumulation, e.g., characterized by fibrosis or ascar; inflammatory disorders, erythroid cell associated disorders; geneexpression disorders; and bleeding/clotting disorders.

[0343] The 65552 metalloproteinase molecules also find use in diagnosisof disorders involving an increase or decrease in 65552metalloproteinase expression relative to normal expression, such as aproliferative disorder, a differentiative disorder (e.g., cancer), animmune disorder, an erythroid cell-associated disorder; a motilitydisorder, a vascular disorder, a bleeding or clotting disorder, or adevelopmental disorder. Thus, where expression or activity of 65552metalloproteinase is greater or less than normal, this may indicate thepresence of or a predisposition towards a 65552 metalloproteinasedisorder. The presence of 65552 metalloproteinase RNA or protein, e.g.,by hybridization of a 65552 specific probe or with a 65552 specificantibody, can be used to identify the amount of 65552 present in aparticular cell or tissue, or other biological sample. 65552 activity(protease activity assays, adhesion assays, binding assays,motility/migration assays, vascularization assays, etc.) can be assessedusing the various techniques described herein or otherwise known in theart. Thus, in another embodiment, the invention provides methods andcompositions for detection of 65552 metalloproteinase in tissues thatnormally or do not normally express 65552 metalloproteinase.

[0344] The 65552 molecules and modulators thereof can act as noveltherapeutic agents for controlling one or more of cellular proliferativeand/or differentiative disorders, cardiovascular disorders, blood vesseldisorders as described herein.

[0345] Tissue Distribution of 65552 mRNA

[0346] TaqMan analysis indicates the highest levels of 65552 expressionare in aortic smooth muscle cells, and muscular artery cells. 65552 isalso expressed in adipose tissue, human umbilical vein epithelial cells,diseased aorta cells, and cells of the vein

[0347] Human 65577

[0348] The present invention is based, in part, on the discovery of anovel gene, referenced to herein as 65577, which encodes a matrixmetalloprotease (also referred to herein as a matrix metalloproteinase,or an MMP), which is a member of the reprolysin (M12B) subfamily of theM12 family of metalloproteinase.

[0349] The human 65577 cDNA sequence which is approximately 3445nucleotide residues long including un-translated regions, contains apredicted methionine-initiated coding sequence of about 3243 nucleotideresidues, excluding termination codon (i.e., nucleotide residues 83-3325of SEQ ID NO: 86; 1-3243 of SEQ ID NO: 88). The coding sequence encodesa 1081 amino acid protein having the amino acid sequence SEQ ID NO: 87.

[0350] The 65577 protein contains a significant number of structuralcharacteristics in common with members of the reprolysin (M12B)subfamily of MMPs. Like other members of this subfamily of MMPs, the65577 proteins of the invention can include a peptidase M12B-propeptidedomain having a sequence motif similar to the cysteine switch motif ofthe matrixins, and a reprolysin-like domain containing a zinc bindingsite (e.g., HEXXH; SEQ ID NO: 84). Unlike the other members of thereprolysin (M12B) subfamily of MMPs, the 65577 proteins of the inventiondo not include an EGF-like domain, or a disintigrin domain.

[0351] The term “family” when referring to the protein and nucleic acidmolecules of the invention means two or more proteins or nucleic acidmolecules having a common structural domain or motif and havingsufficient amino acid or nucleotide sequence homology as defined herein.Such family members can be naturally or non-naturally occurring and canbe from either the same or different species. For example, a family cancontain a first protein of human origin as well as other distinctproteins of human origin, or alternatively, can contain homologues ofnon-human origin, e.g., matrix metalloprotease proteins for any speciesdescribed in the art (e.g., Steiner et al. (1995) Mol. Microbiol.16:825-834, and references cited therein). Members of a family can alsohave common functional characteristics.

[0352] Metalloproteases are a group of highly diverse, widelydistributed proteolytic enzymes that depend on bound Ca²⁺ or Zn²⁺ foractivity. Certain metalloproteases can readily utilize Mn²⁺ and Mg²⁺ aswell. About 30 families of metalloproteases are recognized, about halfof which comprise enzymes containing the HEXXH motif (Rawlings et al.(1995) Meth Enzymol 248:183-228) (SEQ ID NO: 84). The most thoroughlycharacterized of the metalloproteases is thermolysin, a member of the M4metalloprotease family.

[0353] Another metalloprotease family, the M12 family, contains thereprolysin (M12B) subfamily, which contains the snake venommetalloproteases and adamalysins family. The known members of thereprolysin subfamily mostly lack essential peptidase active sites, buttypically contain a putative zinc-chelating sequence HELGHNLGMKH (SEQ IDNO: 93), characteristic for the reprolysin family ofzinc-metalloproteinases. The reprolysin family also contains sixcysteine residues in standard positions for this group of proteinssuggesting disulfide bonding (Leonardi A J et al. (1999)Chromatogrphy;852 (1):237-43). These include BRCA1, a human breastcancer-associated protein, and mammalian fertilin.

[0354] In addition, there is a propeptide region for members of thepeptidase family M12B. The propeptide contains a sequence motif similarto the “cysteine switch” of the matrixins. Matrix metalloproteinases”are expressed as latent proenzymes that are activated by proteolyticcleavage that triggers a conformational change in the propeptide(cysteine switch) model, in which coordination of Zn²⁺ in the activesite of the catalytic domain by a cysteine residue in the prodomain iscritical for inhibition of the protease. (Overgaard et al. (1999) JBiol. Chem, 7:274(19):13427-33).

[0355] In general, the biological functions of metalloproteases includeprotein maturation, degradation of proteins, such as extracellularmatrix proteins, tumor growth, metastasis and angiogenesis, amongothers. Thus, metalloproteases are likely to play important roles in awide range of diseases including, but not limited to, cancer, arthritis,Alzheimer's disease, and a variety of inflammatory conditions othernormal and pathological processes in which matrixmetalloproteinase-catalyzed changes in extracellular matrix proteinstructures have been implicated are described, for example in Nagase etal. (1999) J. Biol. Chem. 274:21491-21494. Accordingly, metalloproteasesare an important target for drug action and development. Therefore, itis valuable to the field of pharmaceutical development to identify andcharacterize previously unknown metalloproteases.

[0356] 65577 proteins of the invention can have signal sequences. Asused herein, a “signal sequence” includes a peptide of at least about 40or 50 amino acid residues in length which occurs at the N-terminus ofsecretory and membrane-bound proteins and which contains at least about70% hydrophobic amino acid residues such as alanine, leucine,isoleucine, phenylalanine, proline, tyrosine, tryptophan, or valine. Ina preferred embodiment, a signal sequence contains at least about 20 to60 amino acid residues, preferably about 30-50 amino acid residues, morepreferably about 47 amino acid residues, and has at least about 60-80%,more preferably 65-75%, and more preferably at least about 70%hydrophobic residues. A signal sequence serves to direct a proteincontaining such a sequence to a lipid bilayer. Thus, in one embodiment,a 65577 protein contains a signal sequence at about amino acids 1 to 47of SEQ ID NO: 87. The signal sequence is cleaved during processing ofthe mature protein.

[0357] In one embodiment, a 65577 protein exists in a mature form whichdoes not include a signal sequence (e.g., in a form which does notinclude residues 1 to about 47 of SEQ ID NO: 87). In this embodiment,the 65577 protein can have a length of about 1035 (e.g., 1027, 1028,1029, 1030, 1031, 1032, 1033, 1034, 1035, 1036, 1037) amino acidresidues, corresponding to a protein having an amino terminus at aboutresidue 48 and having a carboxyl terminus at about residue 1081 of SEQID NO: 87.

[0358] In another embodiment, rather than a signal sequence at aboutresidues 1 to 47 of SEQ ID NO: 87, a 65577 protein may include at leastone transmembrane domain at about amino acid residues 31 to 47 of SEQ IDNO: 87. As used herein, the term “transmembrane domain” includes anamino acid sequence of about 5 amino acid residues in length that spansthe plasma membrane. More preferably, a transmembrane domain includesabout at least 10, 15, 20 or 22 amino acid residues and spans amembrane. Transmembrane domains are rich in hydrophobic residues, andtypically have an alpha-helical structure. In a preferred embodiment, atleast, 60%, 70%, 80%, 90%, 95%, 99% or 100% or more of the amino acidsof a transmembrane domain are hydrophobic, e.g., leucines, isoleucines,tyrosines, or tryptophans. Transmembrane domains are described in, forexample, Zagotta W. N. et al. (1996) Annu. Rev. Neurosci. 19: 235-263,the:contents of which are incorporated herein by reference. Thus, aminoacid residues 31 to 47, 153-169 and 331-347 of SEQ ID NO: 87 canalternatively comprise transmembrane domains in a 65577 protein.

[0359] A human 65577 polypeptide can also include various other domainsor regions. A 65577 polypeptide can also include a peptidase M12Bpropeptide domain. As used herein, the term “peptidase M12B propeptidedomain” refers to a protein domain having an amino acid sequence ofabout 40-160 amino acid residues in length, preferably between about60-150 amino acid residues, more preferably between about 80-130 aminoacid residues, and even more preferably between about 100-120 amino acidresidues, and a bit score of about 30 or greater, preferably 40 orgreater, and most preferably 50 or greater, and an E-value of about2.3e-10 or less, more preferably about 2.3e-1 1 or less, and mostpreferably about 2.3e-12 or less when aligned with a M12B peptidasepropeptide domain (SEQ ID NO: 89) derived from a hidden Markov model(HMM) with PFAM (PFAM Accession No. PF01562. The M12B propeptide domainin 65577 has a bit score of 57.8, and an e-value of 2.3e-13 when alignedto this consensus sequence. An alignment of the 65577 protein withconsensus peptidase M12B propeptide amino acid sequence (SEQ ID NO: 89)(PFAM Accession No. PF01562) derived from a hidden Markov model showsthat a peptidase M12B propeptide domain of 65577 appears at aboutresidues 109-234 of SEQ ID NO: 87.

[0360] In a preferred embodiment, a 65577 polypeptide or protein has apeptidase M12B propeptide domain or a region which includes at leastabout 50-175 amino acids, preferably about 75-150 amino acids, morepreferably about 100-125 amino acids, even more preferably about 110-120amino acid residues and has at least about 60%, 70%, 80%, 90%, 95%, 99%,or 100% identity with a peptidase M12B propeptide domain, e.g., thepeptidase M12B propeptide domain of human 65577 (e.g., residues 109-234of SEQ ID NO: 87).

[0361] The peptidase M12B propeptide domain contains conservedcysteines, any one of which can be involved in the “cysteine switch”mechanism of action of these family members. It is believed thatmetalloproteinases exist in a latent form. Evidence suggests that thislatency is the result of formation of an intramolecular complex betweenthe single cysteine residue in its propeptide domain (referred to hereinas the peptidase M12B propeptide domain) and the essential zinc atom inthe catalytic domain (referred to herein as a reprolysin-like domain), acomplex that blocks the active site. Latent metalloproteinase in thepresence-of matrix degrading enzyme (i.e. collagenase) can be activatedby multiple means, all of which effect the dissociation of the cysteineresidue from the complex. This is referred to as the “cysteine-switch”mechanism of activation. The reprolysin-like domain contains the typicalHEXXH motif (SEQ ID NO: 84), characteristic of enzymes that cleavepeptides. The histidines are positioned close together and act as zincligands, that are required for catalysis. The propeptide domain thatcontains the critical cysteine residue, and the catalytic domain thatcontains the zinc-binding site are the only two domains common to all ofthe MMPs. The amino acid sequences surrounding both the criticalcysteine residue and a region of the protein chains containing two ofthe putative histidine zinc-binding ligands are highly conserved in allof the MMPs. (Van Wart et al., (1990) Proc Natl Acad SciUSA;87(14):5578-82).

[0362] To identify the presence of a peptidase M12B propeptide domainprofiles in a 65577 protein, the amino acid sequence of the protein issearched against a database of HMMs (e.g., the Pfam database, release2.1) using the default parameters. For example, the hmmsf program, whichis available as part of the HMMER package of search programs, is afamily specific default program for MWLPAT0063 and score of 15 is thedefault threshold score for determining a hit.

[0363] For further characterization of 65577 molecule of the inventionas a matrix metalloprotease, the peptide sequence is searched against adatabase of proteins. An alignment of amino acid residues 1-1081 ofhuman 65577 (SEQ ID NO: 87) with amino acid residues 1-1235 of a humanmetalloproteinase (SEQ ID NO: 91) (TrEMBL:O95428) demonstrates thatthese sequences are 19.0% identical using a BLOSUM 50 scoring matrix andgap penalties of −12/2.

[0364] A 65577 protein can also include a reprolysin-like domain, whichis the catalytic domain of the protein. As used herein, the term“reprolysin-like domain” refers to a protein domain having an amino acidsequence of about 100-300 amino-acid residues in length, preferablyabout 150-250 amino acid residues, more preferably about 175-225 aminoacid residues, and even more preferably about 205-220 amino acidresidues, and has a bit score of −50 or greater, preferably −40 orgreater, and most preferably −30 or greater, and an E-value of about 1.8e-3 or less, more preferably about 1.8 e-4 or less, and most preferablyabout 1.8-5 or less when aligned with a consensus reprolysin amino acidsequence (SEQ ID NO: 90) from a hidden Markov model (HMM) within PFAM(PFAM Accession No. PF01421). The reprolysin-like domain in 65577 aspredicted by PFAM has a bit score of −28.2, and and E value of 1.8e-6.An alignment of the 65577 protein with the consensus reprolysin aminoacid sequence (SEQ ID NO: 90) within PFAM (PFAM Accession No. PF01421)shows that a reprolysin-like domain of 65577 appears at residues 295 to497 of SEQ ID NO: 87.

[0365] The reprolysin-like domain typically includes the followingconsensus sequence:[GSTALIVN]-x(2)-H-E-[LIVMFYW]-{DEHRKP}-H-x-[LIVMFYWGSPQ] (SEQ ID NO: 92)(PROSITE Pattern PDOC00129).

[0366] In this consensus sequence pattern, each element in the patternis separated by a dash (-); square [] brackets indicate the particularresidues that are accepted at that position; x indicates any residue isaccepted at that position; a whole number in parenthesis following an xindicates any amino acid repetition of a particular element is acceptedfor that specified number of residues i.e. x(2); {} brackets indicatethat the particular amino acid in that position can be any except thoseenclosed in the bracket.

[0367] The 65577 polypeptide of the invention contains a reprolysin-likeconsensus sequence at amino acid residues 432 to 441 of SEQ ID NO: 87which represents 90% of the reprolysin consensus pattern described inPROSITE pattern PDOC00129. The reprolysin consensus sequence of the65577 polypeptide differs at amino acid residue 437 of SEQ ID NO: 87,wherein an “S” is substituted for any of the “LIVMFY or W” residuescharacteristic of this sequence. The two histidines in this consensussequence bind zinc and are part of the conserved HEXXH motif (SEQ ID NO:84). The HEXXH motif is located at about amino acid residues 435 to 439of SEQ ID NO: 87.

[0368] In a preferred embodiment, a 65577 polypeptide or protein has areprolysin-like domain or a region which includes at least about 90-270amino acids, preferably about 135-225 amino acids, more preferably about155-200 amino acids, even more preferably about 175-185 amino acidresidues and has at least about 60%, 70%, 80%, 90%, 95%, 99%, or 100%identity with a reprolysin domain, e.g., the reprolysin-like domain ofhuman 65577 (e.g., residues 295 to 497 of SEQ ID NO: 87).

[0369] The reprolysin domain is characteristic of extracellularmetalloproteases, such as collagenase and stromelysin, which degrade theextracellular matrix. The members of this family are enzymes that cleavepeptides. These proteases require zinc for catalysis, ligands for whichcan be histidine residues. Members of this family containing thereprolysin domain are also known as adamalysins.

[0370] To identify the presence of a reprolysin-like domain profile in a65577 protein, the amino acid sequence of the protein is searchedagainst a database of HMMs (e.g., the Pfam database, release 2.1) usingthe default parameters. For example, the hmmsf program, which isavailable as part of the HMMER package of search programs, is a family,specific default program for MILPAT0063 and score of 15 is the defaultthreshold score for determining a hit.

[0371] The human 65577 protein has six predicted N-glycosylation sites(Pfam Accession number PS00001) at about amino acid residues 151-154,190-193, 313-316, 744-747, 837-840, and 908-911 of SEQ ID NO: 87; onecAMP and cGMP-dependent protein kinase phosphorylation sites (PFAMAccession Number PS00004) at about amino acid residues 86-89 of SEQ IDNO: 87; fourteen predicted protein kinase C phosphorylation sites (PFAMAccession Number PS00005) at about amino acid residues 135-137, 171-173,220-222, 279-281, 289-291, 395-397, 453-455, 630-623, 697-699, 746-748,794-796, 870-872, 913-915 and 952-954 of SEQ ID NO: 87; nine predictedcasein kinase II phosphorylation sites (PFAM Accession Number PS00006)located at about amino acid residues 65-68, 206-209, 389-392, 420-423,676-676, 816-819, 1020-1023, 1024-1027 and 1059-1062 of SEQ ID NO: 87;one tyrosine kinase phosphorylation site (PFAM Accession Number PS00007)at about amino acid residues 263-270 of SEQ ID NO: 87; sixteen predictedN-myristoylation sites (PFAM Accession Number PS00008) at about aminoacid residues 73-78, 131-136, 167-172, 219-224, 312-317, 331-336,353-358, 426-431, 562-567, 589-584, 738-743, 752-757, 865-870, 890-895,948-953 and 1041-1046 of SEQ ID NO: 87; and three predicted amidationsites (PFAM Accession Number PS00009) at about amino acid residues83-86, 1254-257 and 378-381 of SEQ ID NO: 87.

[0372] General information regarding PFAM identifiers, PS prefix and PFprefix domain identification numbers can be found at Sonnhammer et al.(1997) Protein 28:405-420.

[0373] In one embodiment of the invention, a 65577 polypeptide includesat least one reprolysin-like domain. In another embodiment, the 65577polypeptide includes at least one reprolysin-like domain and at leastone peptidase M12B propeptide domain. In still another embodiment, the65577 polypeptide contains at least one reprolysin-like domain, at leastone peptidase M12B propeptide domain, and at least one transmembranedomain.

[0374] The 65577 molecules of the present invention can further includeone or more of the N-glycosylation, cAMP and cGMP-dependent proteinkinase phosphorylation, protein kinase C phosphorylation, casein kinaseII phosphorylation, tyrosine kinase phosphorylation, N-myristoylation,and amidation sites described herein.

[0375] Because the 65577 polypeptides of the invention can modulate65577 activities, they can be used to develop novel diagnostic andtherapeutic agents for 65577-mediated or related disorders, as describedherein.

[0376] As used herein, a “65577 activity,” “biological activity of65577,” or “functional activity of 65577,” refers to an activity exerted(directly or indirectly) by a 65577 protein, polypeptide or nucleic acidmolecule on, for example, a 65577-responsive cell or on a 65577substrate (e.g., a protein substrate) as determined in vivo or in vitro.In one embodiment, a 65577 activity is a direct activity, such asassociation with a 65577 target molecule. A “target molecule” or“binding partner” of a 65577 protein is a molecule with which the 65577protein binds or interacts in nature. In an exemplary embodiment, such atarget molecule is a 65577 receptor (e.g. an ECM protein). A 65577activity can also be an indirect activity, such as a cellular signalingactivity mediated by interaction of the 65577 protein with a 65577receptor.

[0377] The 65577 molecules of the present invention have similarbiological activities as other MMP family members. For example, the65577 proteins of the present invention can have (directly orindirectly) any one or more of the following activities: (1) the abilityto cleave or modulate the degredation of proteins or peptides of theextracellular matrix in cells of the cardiovascular system. Examples ofsuch cells in which the 65577 molecule can act include arterial cells(e.g., arterial smooth muscle cells (e.g., coronary arterial smoothmuscle cells)), and venous cells (e.g., venous smooth muscle cells); (2)the ability to cleave or modulate the degradation of peptides in cellsof the central nervous system (e.g., brain cortex, spinal cord (e.g.,schwann cells, neuronal cells, and glial cells (e.g., astrocytes)); (3)the ability to catalyze or modulate catalysis of cleavage of covalentbonds within or between amino acid residues, e.g., in ECM, cell-surface,and extracellular proteins; (4) the ability to degrade ECM; (5) theability to modulate angiogenesis; (6) the ability to modulate neuritegrowth; (7) the ability to modulate tumor cell invasion or metastasis;(8) the ability to modulate tissue or organ integrity; (9) the abilityto modulate wound healing; (10) the ability to modulate endometrialcycling; (11) the ability to modulate hair follicle cycling; (12) theability to modulate bone remodeling; (13) the ability to modulateovulation; (14) the ability to modulate embryonic development; and (15)the ability to modulate apoptosis.

[0378] Other activities of the 65577 molecules of the invention includethe ability to modulate function, survival, morphology, proliferationand/or differentiation of cells of tissues in which 65577 molecules areexpressed. Thus, the 65577 molecules can act as novel diagnostic targetsand therapeutic agents for controlling disorders involving aberrantactivities of these cells.

[0379] Still other activities of the 65577 molecules of the inventioninclude the ability to cleave a protein substrate by hydrolysis of anamide bond. Typically, this ability of the molecules of the invention tocleave a protein substrate depends upon the presence of a metal ion,such as zinc. Thus, a 65577 molecule or subsequence or variant havingmetalloproteinase activity is capable of cleaving one or more proteinsubstrates in the presence of a metal, e.g., zinc. Thus, a 65577metalloprotease or subsequence or variant can cleave one or more proteinsubstrates in the presence of zinc.

[0380] Activity assays for the metalloproteinase family members, such as65577 polypeptides, involve any of the known metalloproteinase,reprolysin, or peptidase M12B propeptide activity or functions, as wellas activities/functions that may not typically be found in othermetalloproteinases. These assays include assays which test the abilityto modulate (directly or indirectly) any one or more of the followingMMP functions: (1) the ability to cleave or modulate the degradationproteins or peptides of the extracellular matrix in cells of thecardiovascular system. Examples of such cells in which the 65577molecule can act include arterial cells (e.g., arterial smooth musclecells (e.g., coronary arterial smooth muscle cells)), and venous cells(e.g., venous smooth muscle cells); (2) the ability to cleave ormodulate the degradation of peptides in cells of the central nervoussystem (e.g., brain cortex, spinal cord (e.g., schwann cells, neuronalcells, and glial cells (e.g. astrocytes)); (3) binding ECM; (4) bindingcollagen or gelatin; (5) binding integrin; (6) binding zinc or othermetals; (7) binding a2-macroglobulin; (8) cleaving specific peptidesubstrates to produce fragments,-affecting cell adhesion; (9) bindingheparin or other sulfated glycosaminoglycan, such as heparan sulfate;(10) modulating vascularization or vascular endothelial growth; (11breaking down cartilage; (12) induceing apoptosis of endothelial cells;(13) suppressing tumor growth; (14) modulating angiogenesis; (15)affecting cellular chemotaxis; (16) affecting cell-cell adhesion orcell-matrix interaction; (17) and any of the other biological orfunctional properties of these proteins, including, but not limited to,those disclosed herein, and in the references cited herein. Further,assays can relate to changes in the protein, per se, and on the effectsof these changes, for example, cleavage of the substrate, activation ofthe protein following cleavage, etc. Such assays are described in Tanget al. (1999) FEBS Letters 445:223-225 (for example, induction byinterleukin I in vitro and by intravenous administration oflipopolysaccharide in vivo, as well as effects on cell adhesion,motility, and growth); (Abbaszade et al., (2000)J Biol Chem.18;275(33):25791-7) (for example, products resulting from cleavage atthe Glu-Ala site in cartilage explants and chondrocyte cultures treatedwith interleukin I and retinoic acid, determination of aggrecan cleavingactivity with and without hydroxamate inhibitors); (Kuno and Matsushima(1998) J Biol Chem 273: 13912-13917) (binding to the extracellularmatrix, binding to sulfated glycosaminoglycans, binding to heparansulfate); Kuno et al. (1999) J Biol Chem. June 25;274(26):18821-6(protease trapping of a2-macroglobulin, furin processing); Tortorella etal.(1999) Science;284(5420):1664-6 (detection of aggrecan fragments,especially by neoepitope antibodies, inhibition of cleavage by ADAM-TSinhibitors, inhibition of pro-MMP activation); Vasquez et al., (1998) JAppl Physiol. October;85(4):1421-8 (suppression of fibroblast growthfactor-2-induced vascularization in the cornea pocket assay andinhibition of vascular endothelial growth factor-induced angiogenesis inthe chorioallantoic membrane assay, inhibition of endothelial cellproliferation, competitive inhibition with endostatin, proliferation ofhuman dermal endothelial cells, use of the antiangiogenic region of theTSP-1 motif as bait); (Kuno et al. (1997) J Biol Chem 272: 556-562).;Wolfsberg et al., Dev Biol. (1995) May;169(1):378-83.; Guilpin et al.(1988) J. Biol. Chem. 273:157-166 (α2-macroglobulin trapping, cleavageof prodomain at the furin site to generate active metalloproteinase);Rosendahl et al., (J. Biol. Chem. (1997) 272:24588-24593) (TNF αprocessing). Recombinant assay systems include, but are not limited to,those described in Abbaszade et al., supra; Kuno et al. (1998), supra;Kuno et al. (1999), supra; Tortorella et al., supra; Vasquez et al.,supra, and Kuno et al. (1997), supra.

[0381] The 65577-molecules find use in modulating the 65577 activitiesdescribed herein. As used herein, the term “modulate” or grammaticalvariations thereof means increasing or decreasing an activity, function,signal or response. That is, the 65577 molecules of the invention affectthe targeted activity in either a positive or negative fashion (e.g.,increase or decrease activity, function, or signal). Accordingly, the65577 molecules can act as novel diagnostic targets and therapeuticagents for controlling disorders involving such activities (e.g.,metalloproteinase activities).

[0382] Thus, 65577 molecules described herein can act as noveldiagnostic targets and therapeutic agents for prognosticating,modulating, diagnosing, preventing, inhibiting, alleviating, or treatingmetalloproteinase-associated disorders

[0383] As used herein, a “metalloproteinase-associated disorder”(MMP-associated disorder) includes a disorder, disease or conditionwhich is characterized by a misregulation of a metalloproteinasemediated activity or by an abnormal metalloproteinase mediated activity.As used herein, a metalloproteinase mediated activity, is an activitymediated or involving a molecule which can cleave a protien or peptidesubstrate in the presence of a metal. (e.g., Ca²⁺, Zn²⁺, Mn²⁺, Mg²⁺).Metalloproteinase-associated disorders can detrimentally affect cellproliferation, cell adhesion, cell motility and migration, tissuestructural integrity (e.g., connective tissue formation andmaintenance), inflammatory response, erythroid cell activity, geneexpression; or angiogenesis and vascularization, among others. Thus,examples of metalloproteinase-associated disorders in which the 65577molecules of the invention can be directly or indirectly involvedinclude cellular proliferative and/or differentiative disorders;disorders associated with undesirable or deficientvascularization/angiogenesis; disorders associated with undesirable ordeficient cell adhesion, motility or migration, including, e.g.,metastasis; disorders associated with undesirable or deficient tissuestructural integrity; disorders associated with undesirableextracellular matrix accumulation, e.g., characterized by fibrosis or ascar; inflammatory disorders, erythroid cell associated disorders; geneexpression disorders; and bleeding/clotting disorders.

[0384] The 65577 molecules also find use in diagnosis of disordersinvolving an increase or decrease in 65577 expression relative to normalexpression, such as a proliferative disorder, a differentiative disorder(e.g., cancer), an immune disorder, an erythroid cell-associateddisorder; a motility disorder, a vascular disorder, a bleeding orclotting disorder, or a developmental disorder. Thus, where expressionor activity of 65577 is greater or less than normal, this may indicatethe presence of or a predisposition towards a 65577 disorder. Thepresence of 65577 RNA or protein, e.g., by hybridization of a 65577specific probe or with a 65577 specific antibody, can be used toidentify the amount of 65577 present in a particular cell or tissue, orother biological sample. 65577 activity (protease activity assays,adhesion assays, binding assays, motility/migration assays,vascularization assays, etc.) can be assessed using the varioustechniques described herein or otherwise known in the art. Thus, inanother embodiment, the invention provides methods and compositions fordetection of 65577 in tissues that normally or do not normally express65577.

[0385] The 65577 molecules and modulators thereof can act as noveltherapeutic agents for controlling one or more of cardiovasculardisorders, or neurological disorders as described herein.

[0386] Tissue Distribution of 65577 mRNA

[0387] TaqMan analysis indicates the highest levels of 65577 expressionare in normal artery cells, normal vein cells, aortic and coronarysmooth muscle cells, and human umbilical vein cells. Futhermore, theresults indicate high levels of expression in brain cortex, and spinalcord. 65577 is also expressed at lower levels in in glial cells, normalovary cells, and skin cells

[0388] Definitions

[0389] The 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577 protein, fragments thereof, and derivatives andother variants of the sequence in SEQ ID NO: 2, 5, 12, 21, 26, 30, 36,39, 42, 74, 77 or 87 thereof are collectively referred to as“polypeptides or proteins of the invention” or “27877, 18080, 14081,32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 polypeptides orproteins”. Nucleic acid molecules encoding such polypeptides or proteinsare collectively referred to as “nucleic acids of the invention” or“27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or65577 nucleic acids.”

[0390] As used herein, the term “nucleic acid molecule” includes DNAmolecules (e.g., a cDNA or genomic DNA) and RNA molecules (e.g., anmRNA) and analogs of the DNA or RNA generated, e.g., by the use ofnucleotide analogs. The nucleic acid molecule can be single-stranded ordouble-stranded, but preferably is double-stranded DNA.

[0391] The term “isolated or purified nucleic acid molecule” includesnucleic acid molecules which are separated from other nucleic acidmolecules which are present in the natural source of the nucleic acid.For example, with regards to genomic DNA, the term “isolated” includesnucleic acid molecules which are separated from the chromosome withwhich the genomic DNA is naturally associated. Preferably, an “isolated”nucleic acid is free of sequences which naturally flank the nucleic acid(i.e., sequences located at the 5′ and/or 3′ ends of the nucleic acid)in the genomic DNA of the organism from which the nucleic acid isderived. For example, in various embodiments, the isolated nucleic acidmolecule can contain less than about 5 kb, 4 kb, 3 kb, 2 kb, 1 kb, 0.5kb or 0.1 kb of 5′ and/or 3′ nucleotide sequences which naturally flankthe nucleic acid molecule in genomic DNA of the cell from which thenucleic acid is derived. Moreover, an “isolated” nucleic acid molecule,such as a cDNA molecule, can be substantially free of other cellularmaterial or culture medium when produced by recombinant techniques, orsubstantially free of chemical precursors or other chemicals whenchemically synthesized.

[0392] As used herein, the term “hybridizes under low stringency, mediumstringency, high stringency, or very high stringency conditions”describes conditions for hybridization and washing. Guidance forperforming hybridization reactions can be found in Current Protocols inMolecular Biology (1989) John Wiley & Sons, N.Y., 6.3.1-6.3.6, which isincorporated by reference. Aqueous and nonaqueous methods are describedin that reference and either can be used. Specific hybridizationconditions referred to herein are as follows: 1) low stringencyhybridization conditions in 6× sodium chloride/sodium citrate (SSC) atabout 45° C., followed by two washes in 0.2×SSC, 0.1% SDS at least at50° C. (the temperature of the washes can be increased to 55° C. for lowstringency conditions); 2) medium stringency hybridization conditions in6× SSC at about 45° C., followed by one or more washes in 0.2×SSC, 0.1%SDS at 60° C.; 3) high stringency hybridization conditions in 6× SSC atabout 45° C., followed by one or more washes in 0.2×SSC, 0.1% SDS at 65°C.; and preferably 4) very high stringency hybridization conditions are0.5M sodium phosphate, 7% SDS at 65° C., followed by one or more washesat 0.2×SSC, 1% SDS at 65° C. Very high stringency conditions (4) are thepreferred conditions and the ones that should be used unless otherwisespecified.

[0393] As used herein, a “naturally-occurring” nucleic acid moleculerefers to an RNA or. DNA molecule having a nucleotide sequence thatoccurs in nature (e.g., encodes a natural protein).

[0394] As used herein, the terms “gene” and “recombinant gene” refer tonucleic acid molecules which include an open reading frame encoding a27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or65577 protein, preferably a mammalian 27877, 18080, 14081, 32140, 50352,16658, 14223, 16002, 50566, 65552 or 65577 protein, and can furtherinclude non-coding regulatory sequences, and introns.

[0395] An “isolated” or “purified” polypeptide or protein issubstantially free of cellular material or other contaminating proteinsfrom the cell or tissue source from which the protein is derived, orsubstantially free from chemical precursors or other chemicals whenchemically synthesized. In one embodiment, the language “substantiallyfree” means preparation of 27877, 18080, 14081, 32140, 50352, 16658,14223, 16002, 50566, 65552 or 65577 protein having less than about 30%,20%, 10% and more preferably 5% (by dry weight), of non-27877, 18080,14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 protein(also referred to herein as a “contaminating protein”), or of chemicalprecursors or non-27877, 18080, 14081, 32140, 50352, 16658, 14223,16002, 50566, 65552 or 65577 chemicals. When the 27877, 18080, 14081,32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 protein orbiologically active portion thereof is recombinantly produced, it isalso preferably substantially free of culture medium, i.e., culturemedium represents less than about 20%, more preferably less than about10%, and most preferably less than about 5% of the volume of the proteinpreparation. The invention includes isolated or purified preparations ofat least 0.01, 0.1, 1.0, and 10 milligrams in dry weight.

[0396] A “non-essential” amino acid residue is a residue that can bealtered from the wild-type sequence of 27877, 18080, 14081, 32140,50352, 16658, 14223, 16002, 50566, 65552 or 65577 (e.g., the sequence ofSEQ ID NO: 1, 3, 4, 6, 11, 13, 20, 22, 25, 27, 29, 31, 35, 37, 38, 40,41, 43, 73, 75, 76, 78, 86 or 88) without abolishing or more preferably,without substantially altering a biological activity, whereas an“essential” amino acid residue results in such a change. For example,amino acid residues that are conserved among the polypeptides of thepresent invention, e.g., those present in the conserved domains, arepredicted to be particularly unamenable to alteration.

[0397] A “conservative amino acid substitution” is one in which theamino acid residue is replaced with an amino acid residue having asimilar side chain. Families of amino acid residues having similar sidechains have been defined in the art. These families include amino acidswith basic side chains (e.g., lysine, arginine, histidine), acidic sidechains (e.g., aspartic acid, glutamic acid), uncharged polar side chains(e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine,cysteine), nonpolar side chains (e.g., alanine, valine, leucine,isoleucine, proline, phenylalanine, methionine, tryptophan),beta-branched side chains (e.g., threonine, valine, isoleucine) andaromatic side chains (e.g., tyrosine, phenylalanine, tryptophan,histidine). Thus, a predicted nonessential amino acid residue in a27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or65577 protein is preferably replaced with another amino acid residuefrom the same side chain family. Alternatively, in another embodiment,mutations can be introduced randomly along all or part of a 27877,18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577coding sequence, such as by saturation mutagenesis, and the resultantmutants can be screened for 27877, 18080, 14081, 32140, 50352, 16658,14223, 16002, 50566, 65552 or 65577 biological activity to identifymutants that retain activity. Following mutagenesis of SEQ ID NO: 1, 3,4, 6, 11, 13, 20, 22, 25., 27, 29, 31, 35, 37, 38, 40, 41, 43, 73, 75,76, 78, 86 or 88, the encoded protein can be expressed recombinantly andthe activity of the protein can be determined.

[0398] As used herein, a “biologically active portion” of a 27877,18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577protein includes a fragment of a 27877, 18080, 14081, 32140, 50352,16658, 14223, 16002, 50566, 65552 or 65577 protein which participates inan interaction between a 27877, 18080, 14081, 32140, 50352, 16658,14223, 16002, 50566, 65552 or 65577 molecule and a non-27877, 18080,14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577molecule. Biologically active portions of a 27877, 18080, 14081, 32140,50352, 16658, 14223, 16002, 50566, 65552 or 65577 protein includepeptides comprising amino acid sequences sufficiently homologous to orderived from the amino acid sequence of the 27877, 18080, 14081, 32140,50352, 16658, 14223, 16002, 50566, 65552 or 65577 protein, e.g., theamino acid sequence shown in SEQ ID NO: 2, 5, 12, 21, 26, 30, 36, 39,42, 74, 77 or 87, which include fewer amino acids than the full length27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or65577 protein, and exhibit at least one activity of a 27877, 18080,14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 protein.Typically, biologically active portions comprise a domain or motif withat least one activity of the 27877, 18080, 14081, 32140, 50352, 16658,14223, 16002, 50566, 65552 or 65577 protein. A biologically activeportion of a 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577 protein can be a polypeptide which is, forexample, 10, 25, 50, 100, 200 or more amino acids in length.Biologically active portions of a 27877, 18080, 14081, 32140, 50352,16658, 14223, 16002, 50566, 65552 or 65577 protein can be used astargets for developing agents which modulate a 27877, 18080, 14081,32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 mediatedactivity.

[0399] Calculations of homology or sequence identity (the terms“homology” and “identity” are used interchangeably herein) betweensequences are performed as follows:

[0400] To determine the percent identity of two amino acid sequences, orof two nucleic acid sequences, the sequences are aligned for optimalcomparison purposes (e.g., gaps can be introduced in one or both of afirst and a second amino acid or nucleic acid sequence for optimalalignment and non-homologous sequences can be disregarded for comparisonpurposes). In a preferred embodiment, the length of a reference sequencealigned for comparison purposes is at least 30%, preferably at least40%, more preferably at least 50%, even more preferably at least 60%,and even more preferably at least 70%, 80%, 90%, 100% of the length ofthe reference sequence. The amino acid residues or nucleotides atcorresponding amino acid positions or nucleotide positions are thencompared. When a position in the first sequence is occupied by the sameamino acid residue or nucleotide as the corresponding position in thesecond sequence, then the molecules are identical at that position (asused herein amino acid or nucleic acid “identity” is equivalent to aminoacid or nucleic acid “homology”). The percent identity between the twosequences is a function of the number of identical positions shared bythe sequences, taking into account the number of gaps, and the length ofeach gap, which need to be introduced for optimal alignment of the twosequences.

[0401] The comparison of sequences and determination of percent identitybetween two sequences can be accomplished using a mathematicalalgorithm. In a preferred embodiment, the percent identity between twoamino acid sequences is determined using the Needleman and Wunsch (1970)J. Mol. Biol. 48:444-453 algorithm which has been incorporated into theGAP program in the GCG software package using either a Blossum 62 matrixor a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and alength weight of 1, 2, 3, 4, 5, or 6. In yet another preferredembodiment, the percent identity between two nucleotide sequences isdetermined using the GAP program in the GCG software package using aNWSgapdna.CMP matrix and a gap weight of 40, 50, 60, 70, or 80 and alength weight of 1, 2, 3, 4, 5, or 6. A particularly preferred set ofparameters (and the one that should be used if the practitioner isuncertain about what parameters should be applied to determine if amolecule is within a sequence identity or homology limitation of theinvention) are a Blossum 62 scoring matrix with a gap penalty of 12, agap extend penalty of 4, and a frameshift gap penalty of 5.

[0402] The percent identity between two amino acid or nucleotidesequences can be determined using the algorithm of Meyers and Miller((1989) CABIOS, 4:11-17) which has been incorporated into the ALIGNprogram (version 2.0), using a PAM 120 weight residue table, a gaplength penalty of 12 and a gap penalty of 4.

[0403] The nucleic acid and protein sequences described herein can beused as a “query sequence” to perform a search against public databasesto, for example, identify other family members or related sequences.Such searches can be performed using the NBLAST and XBLAST programs(version 2.0) of Altschul et al. (1990) J. Mol. Biol. 215:403-10. BLASTnucleotide searches can be performed with the NBLAST program, score=100,wordlength=12 to obtain nucleotide sequences homologous to 27877, 18080,14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 nucleicacid molecules of the invention. BLAST protein searches can be performedwith the XBLAST program, score=50, wordlength=3 to obtain amino acidsequences homologous to 27877, 18080, 14081, 32140, 50352, 16658, 14223,16002, 50566, 65552 or 65577 protein molecules of the invention. Toobtain gapped alignments for comparison purposes, Gapped BLAST can beutilized as described in Altschul et al., (1997) Nucleic Acids Res.25:3389-3402. When utilizing BLAST and Gapped BLAST programs, thedefault parameters of the respective programs (e.g., XBLAST and NBLAST)can be used.

[0404] Particular 27877, 18080, 14081, 32140, 50352, 16658, 14223,16002, 50566, 65552 or 65577 polypeptides of the present invention havean amino acid sequence substantially identical to the amino acidsequence of SEQ ID NO: 2, 5, 12, 21, 26, 30, 36, 39, 42, 74, 77 or 87.In the context of an amino acid sequence, the term “substantiallyidentical” is used herein to refer to a first amino acid that contains asufficient or minimum number of amino acid residues that are i)identical to, or ii) conservative substitutions of aligned amino acidresidues in a second amino acid sequence such that the first and secondamino acid sequences can have a common structural domain and/or commonfunctional activity. For example, amino acid sequences that contain acommon structural domain having at least about 60%, or 65% identity,likely 75% identity, more likely 85%, 90%. 91%, 92%, 93%, 94%, 95%, 96%,97%, 98% or 99% identity to SEQ ID NO: 2, 5, 12, 21, 26, 30, 36, 39, 42,74, 77 or 87 are termed substantially identical.

[0405] In the context of nucleotide sequence, the term “substantiallyidentical” is used herein to refer to a first nucleic acid sequence thatcontains a sufficient or minimum number of nucleotides that areidentical to aligned nucleotides in a second nucleic acid sequence suchthat the first and second nucleotide sequences encode a polypeptidehaving common functional activity, or encode a common structuralpolypeptide domain or a common functional polypeptide activity. Forexample, nucleotide sequences having at least about 60%, or 65%identity, likely 75% identity, more likely 85%, 90%. 91%, 92%, 93%, 94%,95%,96%, 97%, 98% or 99% identity to SEQ IDNO: 1, 3, 4, 6, 11, 13, 20,22, 25, 27, 29, 31, 35, 37, 38, 40, 41, 43, 73, 75, 76, 78, 86 or 88 aretermed substantially identical.

[0406] “Misexpression or aberrant expression”, as used herein, refers toa non-wild type pattern of gene expression, at the RNA or protein level.It includes: expression at non-wild type levels, i.e., over or underexpression; a pattern of expression that differs from wild type in termsof the time or stage at which the gene is expressed, e.g., increased ordecreased expression (as compared with wild type) at a predetermineddevelopmental period or stage; a pattern of expression that differs fromwild type in terms of decreased expression (as compared with wild type)in a predetermined cell type or tissue type; a pattern of expressionthat differs from wild type in terms of the splicing size, amino acidsequence, post-transitional modification, or biological activity of theexpressed polypeptide; a pattern of expression that differs from wildtype in terms of the effect of an environmental stimulus orextracellular stimulus on expression of the gene, e.g., a pattern ofincreased or decreased expression (as compared with wild type) in thepresence of an increase or decrease in the strength of the stimulus.

[0407] “Subject”, as used herein, can refer to a mammal, e.g., a human,or to an experimental or animal or disease model. The subject can alsobe a non-human animal, e.g., a horse, cow, goat, or other domesticanimal.

[0408] A “purified preparation of cells”, as used herein, refers to, inthe case of plant or animal cells, an in vitro preparation of cells andnot an entire intact plant or animal. In the case of cultured cells ormicrobial cells, it consists of a preparation of at least 10% and morepreferably 50% of the subject cells.

[0409] As used herein, cellular proliferative and/or differentiativedisorders include cancer, e.g., carcinoma, sarcoma, metastatic disordersor hematopoietic neoplastic disorders, e.g., leukemias. A metastatictumor can arise from a multitude of primary tumor types, including butnot limited to those of prostate, colon, lung, breast and liver origin.

[0410] As used herein, the term “cancer” (also used interchangeably withthe terms, “hyperproliferative” and “neoplastic”) refers to cells havingthe capacity for autonomous growth, i.e., an abnormal state or conditioncharacterized by rapidly proliferating cell growth. Cancerous diseasestates may be categorized as pathologic, i.e., characterizing orconstituting a disease state, e.g., malignant tumor growth, or may becategorized as non-pathologic, i.e., a deviation from normal but notassociated with a disease state, e.g., cell proliferation associatedwith wound repair. The term is meant to include all types of cancerousgrowths or oncogenic processes, metastatic tissues or malignantlytransformed cells, tissues, or organs, irrespective of histopathologictype or stage of invasiveness. The term “cancer” includes malignanciesof the various organ systems, such as those affecting lung, breast,thyroid, lymphoid, gastrointestinal, and genito-urinary tract, as wellas adenocarcinomas which include malignancies such as most coloncancers, renal-cell carcinoma, prostate cancer and/or testicular tumors,non-small cell carcinoma of the lung, cancer of the small intestine andcancer of the esophagus. The term “carcinoma” is art recognized andrefers to malignancies of epithelial or endocrine tissues includingrespiratory system carcinomas, gastrointestinal system carcinomas,genitourinary system carcinomas, testicular carcinomas, breastcarcinomas, prostatic carcinomas, endocrine system carcinomas, andmelanomas. Exemplary carcinomas include those forming from tissue of thecervix, lung, prostate, breast, head and neck, colon and ovary. The term“carcinoma” also includes carcinosarcomas, e.g., which include malignanttumors composed of carcinomatous and sarcomatous tissues. An“adenocarcinoma” refers to a carcinoma derived from glandular tissue orin which the tumor cells form recognizable glandular structures. Theterm “sarcoma” is art recognized and refers to malignant tumors ofmesenchymal derivation.

[0411] Examples of cellular proliferative and/or differentiativedisorders of the lung include, but are not limited to, tumors such asbronchogenic carcinoma, including paraneoplastic syndromes,bronchioloalveolar carcinoma, neuroendocrine tumors, such as bronchialcarcinoid, miscellaneous tumors, metastatic tumors, and pleural tumors,including solitary fibrous tumors (pleural fibroma) and malignantmesothelioma.

[0412] Examples of cellular proliferative and/or differentiativedisorders of the breast include, but are not limited to, proliferativebreast disease including, e.g., epithelial hyperplasia, sclerosingadenosis, and small duct papillomas; tumors, e.g., stromal tumors suchas fibroadenoma, phyllodes tumor, and sarcomas, and epithelial tumorssuch as large duct papilloma; carcinoma of the breast including in situ(noninvasive) carcinoma that includes ductal carcinoma in situ(including Paget's disease) and lobular carcinoma in situ, and invasive(infiltrating) carcinoma including, but not limited to, invasive ductalcarcinoma, invasive lobular carcinoma, medullary carcinoma, colloid(mucinous) carcinoma, tubular carcinoma, and invasive papillarycarcinoma, and miscellaneous malignant neoplasms. Disorders in the malebreast include, but are not limited to, gynecomastia and carcinoma.

[0413] Examples of cellular proliferative and/or differentiativedisorders involving the colon include, but are not limited to, tumors ofthe colon, such as non-neoplastic polyps, adenomas, familial syndromes,colorectal carcinogenesis, colorectal carcinoma, and carcinoid tumors.

[0414] Examples of cancers or neoplastic conditions, in addition to theones described above, include, but are not limited to, a fibrosarcoma,myosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma,angiosarcoma, endotheliosarcoma, lymphangiosarcoma,lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor,leiomyosarcoma, rhabdomyosarcoma, gastric cancer, esophageal cancer,rectal cancer, pancreatic cancer, ovarian cancer, prostate cancer,uterine cancer, cancer of the head and neck, skin cancer, brain cancer,squamous cell carcinoma, sebaceous gland carcinoma, papillary carcinoma,papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma,bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile ductcarcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilm's tumor,cervical cancer, testicular cancer, small cell lung carcinoma, non-smallcell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma,astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma,hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma,melanoma, neuroblastoma, retinoblastoma, leukemia, lymphoma, or Kaposisarcoma.

[0415] Proliferative disorders include hematopoietic neoplasticdisorders. As used herein, the term “hematopoietic neoplastic disorders”includes diseases involving hyperplastic/neoplastic cells ofhematopoietic origin, e.g., arising from myeloid, lymphoid or erythroidlineages, or precursor cells thereof. Preferably, the diseases arisefrom poorly differentiated acute leukemias, e.g., erythroblasticleukemia and acute megakaryoblastic leukemia. Additional exemplarymyeloid disorders include, but are not limited to, acute promyeloidleukemia (APML), acute myelogenous leukemia (AML) and chronicmyelogenous leukemia (CML) (reviewed in Vaickus (1991) Crit Rev. inOncol./Hemotol. 11:267-97); lymphoid malignancies include, but are notlimited to acute lymphoblastic leukemia (ALL) which includes B-lineageALL and T-lineage ALL, chronic lymphocytic leukemia (CLL),prolymphocytic leukemia (PLL), hairy cell leukemia (HLL) andWaldenstrom's macroglobulinemia (WM). Additional forms of malignantlymphomas include, but are not limited to non-Hodgkin lymphoma andvariants thereof, peripheral T cell lymphomas, adult T cellleukemia/lymphoma (ATL), cutaneous T-cell lymphoma (CTCL), largegranular lymphocytic leukemia (LGF), Hodgkin's disease andReed-Sternberg disease.

[0416] As used herein, an “angiogenesis disorder” includes a disease ordisorder which affects or is caused by aberrant or deficientangiogenesis. Disorders involving angiogenesis include, but are notlimited to, aberrant or excess angiogenesis in tumors such ashemangiomas and Kaposi's sarcoma, von Hippel-Lindau disease, as well asthe angiogenesis associated with tumor growth; aberrant or excessangiogenesis in diseases such as a Castleman's disease or fibrodysplasiaossificans progressiva; aberrant or deficient angiogenesis associatedwith aging, complications of healing certain wounds and complications ofdiseases such as diabetes and rheumatoid arthritis; or aberrant ordeficient angiogenesis associated with hereditary hemorrhagictelangiectasia, autosomal dominant polycystic kidney disease,myelodysplastic syndrome or Klippel-Trenaunay-Weber syndrome.

[0417] As used herein, disorders of the breast include, but are notlimited to, disorders of development; inflammations, including but notlimited to, acute mastitis, periductal mastitis, periductal mastitis(recurrent subareolar abscess, squamous metaplasia of lactiferousducts), mammary duct ectasia, fat necrosis, granulomatous mastitis, andpathologies associated with silicone breast implants; fibrocysticchanges; proliferative breast disease including, but not limited to,epithelial hyperplasia, sclerosing adenosis, and small duct papillomas;tumors including, but not limited to, stromal tumors such asfibroadenoma, phyllodes tumor, and sarcomas, and epithelial tumors suchas large duct papilloma; carcinoma of the breast including in situ(noninvasive) carcinoma that includes ductal carcinoma in situ(including Paget's disease) and lobular carcinoma in situ, and invasive(infiltrating) carcinoma including, but not limited to, invasive ductalcarcinoma, no special type, invasive lobular carcinoma, medullarycarcinoma, colloid (mucinous) carcinoma, tubular carcinoma, and invasivepapillary carcinoma, and miscellaneous malignant neoplasms. Disorders inthe male breast include, but are not limited to, gynecomastia andcarcinoma.

[0418] As used herein, disorders involving the colon include, but arenot limited to, congenital anomalies, such as atresia and stenosis,Meckel diverticulum, congenital aganglionic megacolon-Hirschsprungdisease; enterocolitis, such as diarrhea and dysentery, infectiousenterocolitis, including viral gastroenteritis, bacterial enterocolitis,necrotizing enterocolitis, antibiotic-associated colitis(pseudomembranous colitis), and collagenous and lymphocytic colitis,miscellaneous intestinal inflammatory disorders, including parasites andprotozoa, acquired immunodeficiency syndrome, transplantation,drug-induced intestinal injury, radiation enterocolitis, neutropeniccolitis (typhlitis), and diversion colitis; idiopathic inflammatorybowel disease, such as Crohn disease and ulcerative colitis; tumors ofthe colon, such as non-neoplastic polyps, adenomas, familial syndromes,colorectal carcinogenesis, colorectal carcinoma, and carcinoid tumors.

[0419] As used herein, disorders involving the kidney include, but arenot limited to, congenital anomalies including, but not limited to,cystic diseases of the kidney, that include but are not limited to,cystic renal dysplasia, autosomal dominant (adult) polycystic kidneydisease, autosomal recessive (childhood) polycystic kidney disease, andcystic diseases of renal medulla, which include, but are not limited to,medullary sponge kidney, and nephronophthisis-uremic medullary cysticdisease complex, acquired (dialysis-associated) cystic disease, such assimple cysts; glomerular diseases including pathologies of glomerularinjury that include, but are not limited to, in situ immune complexdeposition, that includes, but is not limited to, anti-GBM nephritis,Heymann nephritis, and antibodies against planted antigens, circulatingimmune complex nephritis, antibodies to glomerular cells, cell-mediatedimmunity in glomeruloneptritis, activation of alternative complementpathway, epithelial cell injury, and pathologies involving mediators ofglomerular injury including cellular and soluble mediators, acuteglomerulonephritis, such as acute proliferative (poststreptococcal,postinfectious) glomerulonephritis, including but not limited to,poststreptococcal glomerulonephritis and nonstreptococcal acuteglomerulonephritis, rapidly progressive (crescentic) glomerulonephritis,nephrotic syndrome, membranous glomerulonephritis (membranousnephropathy), minimal change disease (lipoid nephrosis), focal segmentalglomerulosclerosis, membranoproliferative glomerulonephritis, IgAnephropathy (Berger disease), focal proliferative and necrotizingglomerulonephritis (focal glomerulonephritis), hereditary nephritis,including but not limited to, Alport syndrome and thin membrane disease(benign familial hematuria), chronic glomerulonephritis, glomerularlesions associated with systemic disease, including but not limited to,systemic lupus erythematosus, Henoch-Schönlein purpura, bacterialendocarditis, diabetic glomerulosclerosis, amyloidosis, fibrillary andimmunotactoid glomerulonephritis, and other systemic disorders; diseasesaffecting tubules and interstitium, including acute tubular necrosis andtubulointerstitial nephritis, including but not limited to,pyelonephritis and urinary tract infection, acute pyelonephritis,chronic pyelonephritis and reflux nephropathy, and tubulointerstitialnephritis induced by drugs and toxins, including but not limited to,acute drug-induced interstitial nephritis, analgesic abuse nephropathy,nephropathy associated with nonsteroidal anti-inflammatory drugs, andother tubulointerstitial diseases including, but not limited to, uratenephropathy, hypercalcemia and nephrocalcinosis, and multiple myeloma;diseases of blood vessels including benign nephrosclerosis, malignanthypertension and accelerated nephrosclerosis, renal artery stenosis, andthrombotic microangiopathies including, but not limited to, classic(childhood) hemolytic-uremic syndrome, adult hemolytic-uremic.syndrome/thrombotic thrombocytopenic purpura, idiopathic HUS/TTP, andother vascular disorders including, but not limited to, atheroscleroticischemic renal disease, atheroembolic renal disease, sickle cell diseasenephropathy, diffuse cortical necrosis, and renal infarcts; urinarytract obstruction (obstructive uropathy); urolithiasis (renal calculi,stones); and tumors of the kidney including, but not limited to, benigntumors, such as renal papillary adenoma, renal fibroma or hamartoma(renomedullary interstitial cell tumor), angiomyolipoma, and oncocytoma,and malignant tumors, including renal cell carcinoma (hypernephroma,adenocarcinoma of kidney), which includes urothelial carcinomas of renalpelvis.

[0420] Examples of disorders of the lung include, but are not limitedto, congenital anomalies; atelectasis; diseases of vascular origin, suchas pulmonary congestion and edema, including hemodynamic pulmonary edemaand edema caused by microvascular injury, adult respiratory distresssyndrome (diffuse alveolar damage), pulmonary embolism, hemorrhage, andinfarction, and pulmonary hypertension and vascular sclerosis; chronicobstructive pulmonary disease, such as emphysema, chronic bronchitis,bronchial asthma, and bronchiectasis; diffuse interstitial(infiltrative, restrictive) diseases, such as pneumoconioses,sarcoidosis, idiopathic pulmonary fibrosis, desquamative interstitialpneumonitis, hypersensitivity pneumonitis, pulmonary eosinophilia(pulmonary infiltration with eosinophilia), Bronchiolitisobliterans-organizing pneumonia, diffuse pulmonary hemorrhage syndromes,including Goodpasture syndrome, idiopathic pulmonary hemosiderosis andother hemorrhagic syndromes, pulmonary involvement in collagen vasculardisorders, and pulmonary alveolar proteinosis; complications oftherapies, such as drug-induced lung disease, radiation-induced lungdisease, and lung transplantation; tumors, such as bronchogeniccarcinoma, including paraneoplastic syndromes, bronchioloalveolarcarcinoma, neuroendocrine tumors, such as bronchial carcinoid,miscellaneous tumors, and metastatic tumors; pathologies of the pleura,including inflammatory pleural effusions, noninflammatory pleuraleffusions, pneumothorax, and pleural tumors, including solitary fibroustumors (pleural fibroma) and malignant mesothelioma.

[0421] As used herein, disorders involving the pancreas include those ofthe exocrine pancreas such as congenital anomalies, including but notlimited to, ectopic pancreas; pancreatitis, including but not limitedto, acute pancreatitis; cysts, including but not limited to,pseudocysts; tumors, including but not limited to, cystic tumors andcarcinoma of the pancreas; and disorders of the endocrine pancreas suchas, diabetes mellitus; islet cell tumors, including but not limited to,insulinomas, gastrinomas, and other rare islet cell tumors.

[0422] As used herein, disorders involving the ovary include, forexample, polycystic ovarian disease, Stein-leventhal syndrome,Pseudomyxoma peritonei and stromal hyperthecosis; ovarian tumors suchas, tumors of coelomic epithelium, serous tumors, mucinous tumors,endometeriod tumors, clear cell adenocarcinoma, cystadenofibroma,brenner tumor, surface epithelial tumors; germ cell tumors such asmature (benign) teratomas, monodermal teratomas, immature malignantteratomas, dysgerminoma, endodermal sinus tumor, choriocarcinoma; sexcord-stomal tumors such as, granulosa-theca cell tumors,thecoma-fibromas, androblastomas, hill cell tumors, and gonadoblastoma;and metastatic tumors such as Krukenberg tumors.

[0423] As used herein, hormonal disorders and diseases include type Iand type II diabetes mellitus, pituitary disorders (e.g., growthdisorders), thyroid disorders (e.g., hypothyroidism or hyperthyroidism),and reproductive or fertility disorders (e.g., disorders which affectthe organs of the reproductive system, e.g., the prostate gland, theuterus, or the vagina; disorders which involve an imbalance in thelevels of a reproductive hormone in a subject; disorders affecting theability of a subject to reproduce; and disorders affecting secondary sexcharacteristic development, e.g., adrenal hyperplasia).

[0424] Aberrant expression and/or activity of the molecules of theinvention can mediate disorders associated with bone metabolism. “Bonemetabolism” refers to direct or indirect effects in the formation ordegeneration of bone structures, e.g., bone formation, bone resorption,etc., which can ultimately affect the concentrations in serum of calciumand phosphate. This term also includes activities mediated by themolecules of the invention in bone cells, e.g. osteoclasts andosteoblasts, that can in turn result in bone formation and degeneration.For example, molecules of the invention can support different activitiesof bone resorbing osteoclasts such as the stimulation of differentiationof monocytes and mononuclear phagocytes into osteoclasts. Accordingly,molecules of the invention that modulate the production of bone cellscan influence bone formation and degeneration, and thus can be used totreat bone disorders. Examples of such disorders include, but are notlimited to, osteoporosis, osteodystrophy, osteomalacia, rickets,osteitis fibrosa cystica, renal osteodystrophy, osteosclerosis,anti-convulsant treatment, osteopenia, fibrogenesis-imperfecta ossium,secondary hyperparathyrodism, hypoparathyroidism, hyperparathyroidism,cirrhosis, obstructive jaundice, drug induced metabolism, medullarycarcinoma, chronic renal disease, rickets, sarcoidosis, glucocorticoidantagonism, malabsorption syndrome, steatorrhea, tropical sprue,idiopathic hypercalcemia and milk fever.

[0425] As used herein, “a prostate disorder” refers to an abnormalcondition occurring in the male pelvic region characterized by, e.g.,male sexual dysfunction and/or urinary symptoms. This disorder may bemanifested in the form of genitourinary inflammation (e.g., inflammationof smooth muscle cells) as in several common diseases of the prostateincluding prostatitis, benign prostatic hyperplasia and cancer, e.g.,adenocarcinoma or carcinoma, of the prostate.

[0426] Examples of immune, e.g., inflammatory, (e.g. respiratoryinflammatory) disorders or diseases include, but are not limited to,autoimmune diseases (including, for example, diabetes mellitus,arthritis (including rheumatoid arthritis, juvenile rheumatoidarthritis, osteoarthritis, psoriatic arthritis), multiple sclerosis,encephalomyelitis, myasthenia gravis, systemic lupus erythematosis,autoimmune thyroiditis, dermatitis (including atopic dermatitis andeczematous dermatitis), psoriasis, Sjogren's Syndrome, inflammatorybowel disease, e.g. Crohn's disease and ulcerative colitis, aphthousulcer, iritis, conjunctivitis, keratoconjunctivitis, asthma, allergicasthma, chronic obstructive pulmonary disease, cutaneous lupuserythematosus, scleroderma, vaginitis, proctitis, drug eruptions,leprosy reversal reactions, erythema nodosum leprosum, autoimmuneuveitis, allergic encephalomyelitis, acute necrotizing hemorrhagicencephalopathy, idiopathic bilateral progressive sensorineural hearingloss, aplastic anemia, pure red cell anemia, idiopathicthrombocytopenia, polychondritis, Wegener's granulomatosis, chronicactive hepatitis, Stevens-Johnson syndrome, idiopathic sprue, lichenplanus, Graves' disease, sarcoidosis, primary biliary cirrhosis, uveitisposterior, and interstitial lung fibrosis), graft-versus-host disease,cases of transplantation, and allergy such as, atopic allergy.

[0427] As used herein, disorders involving the heart, or “cardiovasculardisease” or a “cardiovascular disorder” includes a disease or disorderwhich affects the cardiovascular system, e.g., the heart, the bloodvessels, and/or the blood. A cardiovascular disorder can be caused by animbalance in arterial pressure, a malfunction of the heart, or anocclusion of a blood vessel, e.g., by a thrombus. A cardiovasculardisorder includes, but is not limited to disorders such asarteriosclerosis, atherosclerosis, cardiac hypertrophy, ischemiareperfusion injury, restenosis, arterial inflammation, vascular wallremodeling, ventricular remodeling, rapid ventricular pacing, coronarymicroembolism, tachycardia, bradycardia, pressure overload, aorticbending, coronary artery ligation, vascular heart disease, valvulardisease, including but not limited to, valvular degeneration caused bycalcification, rheumatic heart disease, endocarditis, or complicationsof artificial valves; atrial fibrillation, long-QT syndrome, congestiveheart failure, sinus node dysfunction, angina, heart failure,hypertension, atrial fibrillation, atrial flutter, pericardial disease,including but not limited to, pericardial effusion and pericarditis;cardiomyopathies, e.g., dilated cardiomyopathy or idiopathiccardiomyopathy, myocardial infarction, coronary artery disease, coronaryartery spasm, ischemic disease, arrhythmia, sudden cardiac death, andcardiovascular developmental disorders (e.g., arteriovenousmalformations, arteriovenous fistulae, raynaud's syndrome, neurogenicthoracic outlet syndrome, causalgia/reflex sympathetic dystrophy,hemangioma, aneurysm, cavernous angioma, aortic valve stenosis, atrialseptal defects, atrioventricular canal, coarctation of the aorta,ebsteins anomaly, hypoplastic left heart syndrome, interruption of theaortic arch, mitral valve prolapse, ductus arteriosus, patent foramenovale, partial anomalous pulmonary venous return, pulmonary atresia withventricular septal defect, pulmonary atresia without ventricular septaldefect, persistance of the fetal circulation, pulmonary valve stenosis,single ventricle, total anomalous pulmonary venous return, transpositionof the great vessels, tricuspid atresia, truncus arteriosus, ventricularseptal defects). A cardiovascular disease or disorder also can includean endothelial cell disorder.

[0428] “Procedural vascular trauma” includes the effects ofsurgical/medical-mechanical interventions into mammalian vasculature,but does not include vascular trauma due to the organic vascularpathologies listed hereinabove, or to unintended traumas, such as due toan accident. Thus, procedural vascular traumas within the scope of thepresent treatment method include (1) organ grafting or transplantation,such as transplantation and grafting of heart, kidney, liver and thelike, e.g., involving vessel anastomosis; (2) vascular surgery, such ascoronary bypass surgery, biopsy, heart valve replacement, atheroectomy,thrombectomy, and the like; (3) transcatheter vascular therapies (TVT)including angioplasty, e.g., laser angioplasty and PTCA proceduresdiscussed hereinbelow, employing balloon catheters, or indwellingcatheters; (4) vascular grafting using natural or synthetic materials,such as in saphenous vein coronary bypass grafts, dacron and venousgrafts used for peripheral arterial reconstruction, etc.; (5) placementof a mechanical shunt, such as a PTFE hemodialysis shunt used forarteriovenous communications; and (6) placement of an intravascularstent, which may be metallic, plastic or a biodegradable polymer. SeeU.S. patent application Ser. No. 08/389,712, filed Feb. 15, 1995, whichis incorporated by reference herein. For a general discussion ofimplantable devices and biomaterials from which they can be formed, seeH. Kambic et al., “Biomaterials in Artificial Organs”, Chem. Eng. News,30 (Apr. 14, 1986), the disclosure of which is incorporated by referenceherein.

[0429] Small vessel disease includes, but is not limited to, vascularinsufficiency in the limbs, peripheral neuropathy and retinopathy, e.g.,diabetic retinopathy.

[0430] As used herein, disorders involving the brain include, but arenot limited to, disorders involving neurons, and disorders involvingglia, such as astrocytes, oligodendrocytes, ependymal cells, andmicroglia; cerebral edema, raised intracranial pressure and herniation,and hydrocephalus; malformations and developmental diseases, such asneural tube defects, forebrain anomalies, posterior fossa anomalies, andsyringomyelia and hydromyelia; perinatal brain injury; cerebrovasculardiseases, such as those related to hypoxia, ischemia, and infarction,including hypotension, hypoperfusion, and low-flow states—globalcerebral ischemia and focal cerebral ischemia—infarction fromobstruction of local blood supply, intracranial hemorrhage, includingintracerebral (intraparenchymal) hemorrhage, subarachnoid hemorrhage andruptured berry aneurysms, and vascular malformations, hypertensivecerebrovascular disease, including lacunar infarcts, slit hemorrhages,and hypertensive encephalopathy; infections, such as acute meningitis,including acute pyogenic (bacterial) meningitis and acute aseptic(viral) meningitis, acute focal suppurative infections, including brainabscess, subdural empyema, and extradural abscess, chronic bacterialmeningoencephalitis, including tuberculosis and mycobacterioses,neurosyphilis, and neuroborreliosis (Lyme disease), viralmeningoencephalitis, including arthropod-borne (Arbo) viralencephalitis, Herpes simplex virus Type 1, Herpes simplex virus Type 2,Varicella-zoster virus (Herpes zoster), cytomegalovirus, poliomyelitis,rabies, and human immunodeficiency virus 1, including HIV-1meningoencephalitis (subacute encephalitis), vacuolar myelopathy,AIDS-associated myopathy, peripheral neuropathy, and AIDS in children,progressive multifocal leukoencephalopathy, subacute sclerosingpanencephalitis, fungal meningoencephalitis, other infectious diseasesof the nervous system; transmissible spongiform encephalopathies (priondiseases); demyelinating diseases, including multiple sclerosis,multiple sclerosis variants, acute disseminated encephalomyelitis andacute necrotizing hemorrhagic encephalomyelitis, and other diseases withdemyelination; degenerative diseases, such as degenerative diseasesaffecting the cerebral cortex, including Alzheimer disease and Pickdisease, degenerative diseases of basal ganglia and brain stem,including Parkinsonism, idiopathic Parkinson disease (paralysisagitans), progressive supranuclear palsy, corticobasal degenration,multiple system atrophy, including striatonigral degenration, Shy-Dragersyndrome, and olivopontocerebellar atrophy, and Huntington disease;spinocerebellar degenerations, including spinocerebellar ataxias,including Friedreich ataxia, and ataxia-telanglectasia, degenerativediseases affecting motor neurons, including amyotrophic lateralsclerosis (motor neuron disease), bulbospinal atrophy (Kennedysyndrome), and spinal muscular atrophy; inborn errors of metabolism,such as leukodystrophies, including Krabbe disease, metachromaticleukodystrophy, adrenoleukodystrophy, Pelizaeus-Merzbacher disease, andCanavan disease, mitochondrial encephalomyopathies, including Leighdisease and other mitochondrial encephalomyopathies; toxic and acquiredmetabolic diseases, including vitamin deficiencies such as thiamine(vitamin B₁) deficiency and vitamin B₁₂ deficiency, neurologic sequelaeof metabolic disturbances, including hypoglycemia, hyperglycemia, andhepatic encephatopathy, toxic disorders, including carbon monoxide,methanol, ethanol, and radiation, including combined methotrexate andradiation-induced injury; tumors, such as gliomas, includingastrocytoma, including fibrillary (diffuse) astrocytoma and glioblastomamultiforme, pilocytic astrocytoma, pleomorphic xanthoastrocytoma, andbrain stem glioma, oligodendroglioma, and ependymoma and relatedparaventricular mass lesions, neuronal tumors, poorly differentiatedneoplasms, including medulloblastoma, other parenchymal tumors,including primary brain lymphoma, germ cell tumors, and pinealparenchymal tumors, meningiomas, metastatic tumors, paraneoplasticsyndromes, peripheral nerve sheath tumors, including schwannoma,neurofibroma, and malignant peripheral nerve sheath tumor (malignantschwannoma), and neurocutaneous syndromes (phakomatoses), includingneurofibromotosis, including Type 1 neurofibromatosis (NF1) and TYPE 2neurofibromatosis (NF2), tuberous sclerosis, and Von Hippel-Lindaudisease.

[0431] As used herein, disorders involving blood vessels include, butare not limited to, responses of vascular cell walls to injury, such asendothelial dysfunction and endothelial activation and intimalthickening; vascular diseases including, but not limited to, congenitalanomalies, such as arteriovenous fistula, atherosclerosis, andhypertensive vascular disease, such as hypertension; inflammatorydisease—the vasculitides, such as giant cell (temporal) arteritis,Takayasu arteritis, polyarteritis nodosa (classic), Kawasaki syndrome(mucocutaneous lymph node syndrome), microscopic polyanglitis(microscopic polyarteritis, hypersensitivity or leukocytoclasticanglitis), Wegener granulomatosis, thromboanglitis obliterans (Buergerdisease), vasculitis associated with other disorders, and infectiousarteritis; Raynaud disease; aneurysms and dissection, such as abdominalaortic aneurysms, syphilitic (luetic) aneurysms, and aortic dissection(dissecting hematoma); disorders of veins and lymphatics, such asvaricose veins, thrombophlebitis and phlebothrombosis, obstruction ofsuperior vena cava (superior vena cava syndrome), obstruction ofinferior vena cava (inferior vena cava syndrome), and lymphangitis andlymphedema; tumors, including benign tumors and tumor-like conditions,such as hemangioma, lymphangioma, glomus tumor (glomangioma), vascularectasias, and bacillary angiomatosis, and intermediate-grade (borderlinelow-grade malignant) tumors, such as Kaposi sarcoma andhemangloendothelioma, and malignant tumors, such as angiosarcoma andhemangiopericytoma; and pathology of therapeutic interventions invascular disease, such as balloon angioplasty and related techniques andvascular replacement, such as coronary artery bypass graft surgery.

[0432] As used herein, disorders involving the testis and epididymisinclude, but are not limited to, congenital anomalies such ascryptorchidism, regressive changes such as atrophy, inflammations suchas nonspecific epididymitis and orchitis, granulomatous (autoimmune)orchitis, and specific inflammations including, but not limited to,gonorrhea, mumps, tuberculosis, and syphilis, vascular disturbancesincluding torsion, testicular tumors including germ cell tumors thatinclude, but are not limited to, seminoma, spermatocytic seminoma,embryonal carcinoma, yolk sac tumor choriocarcinoma, teratoma, and mixedtumors, tumore of sex cord-gonadal stroma including, but not limited to,Leydig (interstitial) cell tumors and sertoli cell tumors(androblastoma), and testicular lymphoma, and miscellaneous lesions oftunica vaginalis.

[0433] As used herein, skeletal muscle disorders include, but are notlimited to, muscular dystrophy (e.g., Duchenne muscular dystrophy,Becker muscular dystrophy, Emery-Dreifuss muscular dystrophy,limb-girdle muscular dystrophy, facioscapulohumeral muscular dystrophy,myotonic dystrophy, oculopharyngeal muscular dystrophy, distal musculardystrophy, and congenital muscular dystrophy), motor neuron diseases(e.g., amyotrophic lateral sclerosis, infantile progressive spinalmuscular atrophy, intermediate spinal muscular atrophy, spinal bulbarmuscular atrophy, and adult spinal muscular atrophy), myopathies (e.g.,inflammatory myopathies (e.g., dermatomyositis and polymyositis),myotonia congenita, paramyotonia congenita, central core disease,nemaline myopathy, myotubular myopathy, and periodic paralysis), tumorssuch as rhabdomyosarcoma, and metabolic diseases of muscle (e.g.,phosphorylase deficiency, acid maltase deficiency, phosphofructokinasedeficiency, debrancher enzyme deficiency, mitochondrial myopathy,carnitine deficiency, carnitine palmityl transferase deficiency,phosphoglycerate kinase deficiency, phosphoglycerate mutase deficiency,lactate dehydrogenase deficiency, and myoadenylate deaminasedeficiency).

[0434] As used herein, an “endothelial cell disorder” includes adisorder characterized by aberrant, unregulated, or unwanted endothelialcell activity, e.g., proliferation, migration, angiogenesis, orvascularization; or aberrant expression of cell surface adhesionmolecules or genes associated with angiogenesis, e.g., TIE-2, FLT andFLK. Endothelial cell disorders include tumorigenesis, tumor metastasis,psoriasis, diabetic retinopathy, endometriosis, Grave's disease,ischemic disease (e.g., atherosclerosis), and chronic inflammatorydiseases (e.g., rheumatoid arthritis).

[0435] Disorders which can be treated or diagnosed by methods describedherein include, but are not limited to, disorders associated with anaccumulation in the liver of fibrous tissue, such as that resulting froman imbalance between production and degradation of the extracellularmatrix accompanied by the collapse and condensation of preexistingfibers. The methods described herein can be used to diagnose or treathepatocellular necrosis or injury induced by a wide variety of agentsincluding processes which disturb homeostasis, such as an inflammatoryprocess, tissue damage resulting from toxic injury or altered hepaticblood flow, and infections (e.g., bacterial, viral and parasitic). Forexample, the methods can be used for the early detection of hepaticinjury, such as portal hypertension or hepatic fibrosis. In addition,the methods can be employed to detect liver fibrosis attributed toinborn errors of metabolism, for example, fibrosis resulting from astorage disorder such as Gaucher's disease (lipid abnormalities) or aglycogen storage disease, A1-antitrypsin deficiency; a disordermediating the accumulation (e.g., storage) of an exogenous substance,for example, hemochromatosis (iron-overload syndrome) and copper storagediseases (Wilson's disease), disorders resulting in the accumulation ofa toxic metabolite (e.g., tyrosinemia, fructosemia and galactosemia) andperoxisomal disorders (e.g., Zellweger syndrome). Additionally, themethods described herein can be used for the early detection andtreatment of liver injury associated with the administration of variouschemicals or drugs, such as for example, methotrexate, isonizaid,oxyphenisatin, methyldopa, chlorpromazine, tolbutamide or alcohol, orwhich represents a hepatic manifestation of a vascular disorder such asobstruction of either the intrahepatic or extrahepatic bile flow or analteration in hepatic circulation resulting, for example, from chronicheart failure, veno-occlusive disease, portal vein thrombosis orBudd-Chiari syndrome.

[0436] Additionally, the molecules of the invention can play animportant role in the etiology of certain viral diseases, including butnot limited to Hepatitis B, Hepatitis C and Herpes Simplex Virus (HSV).Modulators of the activity of the molecules of the invention could beused to control viral diseases. The modulators can be used in thetreatment and/or diagnosis of viral infected tissue or virus-associatedtissue fibrosis, especially liver and liver fibrosis. Also, suchmodulators can be used in the treatment and/or diagnosis ofvirus-associated carcinoma, especially hepatocellular cancer.

[0437] As used herein, a “viral pathogen” or “viral pathogen disorder”includes respiratory viral pathogens and their associated disordersinclude, for example, adenovirus, resulting in upper and lowerrespiratory tract infections; conjuctivitis and diarrhea; echovirus,resulting in upper respiratory tract infections, pharyngitis and rash;rhinovirus, resulting in upper respiratory tract infections;cosackievirus, resulting in Pleurodynia, herpangia, hand-foot-mouthdisease; coronavirus, resulting in upper respiratory tract infections;influenza A and B viruses, resulting in influenza; parainfluenza virus1-4, resulting in upper and lower respiratory tract infections andcroup; respiratory syncytial virus, resulting in bronchiolitis andpneumonia. Digestive viral pathogens and their associated disordersinclude, for example, mumps virus, resulting in mumps, pancreatitis, andorchitis; rotavirus, resulting in childhood diarrhea; Norwalk Agent,resulting in gastroenteritis; hepatitis A virus, resulting in acuteviral hepatitis; hepatitis B virus, hepatitis D virus and hepatitis Cvirus, resulting in acute or chronic hepatitis; hepatitis E virus,resulting in enterically transmitted hepatitis. Systemic viral pathogensassociated with disorders involving skin eruptions include, for example,measles virus, resulting in measles (rubeola); rubella virus, resultingin German measles (rubella); parvovirus, resulting in erythemainfectiosum and aplastic anemia; varicella-zoster virus, resulting inchicken pox and shingles; herpes simplex virus 1-associated, resultingin cold sores; and herpes simplex virus 2, resulting in genital herpes.Systemic viral pathogens associated with hematopoietic disordersinclude, for example, cytomegalovirus, resulting in cytomegalicinclusion disease; Epstein-Barr virus, resulting in mononucleosis;HTLV-1 resulting in adult T-cell leukemia and tropical spasticparaparesis; HTLV-II; and HIV 1 and HIV 2, resulting in AIDS. Arboviralpathogens associated with hemorrhagic fevers include, for example,dengue virus 1-4, resulting in dengue and hemorrhagic fever; yellowfever virus, resulting in yellow fever; Colorado tick fever virus,resulting in Colorado tick fever; and regional hemorrhagic feverviruses, resulting in Bolivian, Argentinian, Lassa fever. Viralpathogens associated with warty growths and other hyperplasias include,for example, papillomavirus, resulting in condyloma and cervicalcarcinoma; and molluscum virus, resulting in molluscum.contagiosum.Viral pathogens associated with central nervous system disordersinclude, for example, poliovirus, resulting in poliomyelitis;rabiesvirus, associated with rabies; JC virus, associated withprogressive multifocal leukoencephalophathy; and arboviral encephalitisviruses, resulting in Eastern, Western, Venezuelan, St. Louis, orCalifornia group encephalitis. Viral pathogens associated with cancerinclude, for example, human papillomaviruses, implicated in the genesisof several cancers including squamous cell carcinoma of the cervix andanogenital region, oral cancer and laryngeal cancers; Epstein-Barrvirus, implicated in pathogenesis of the African form of Burkittlymphoma, B-cell lymphomas, Hodgkin disease, and nasopharyngealcarcinomas; hepatitis B virus, implicated in liver cancer; human T-cellleukemia virus type 1 (HTLV-1), associated with T-cellleukemia/lymphoma; and the Kaposi sarcoma herpesvirus (KSHV).

[0438] Disorders related to reduced platelet number, thrombocytopenia,include idiopathic thrombocytopenic purpura, including acute idiopathicthrombocytopenic purpura, drug-induced thrombocytopenia, HIV-associatedthrombocytopenia, and thrombotic microangiopathies: thromboticthrombocytopenic purpura and hemolytic-uremic syndrome.

[0439] As used herein, neurological disorders include disorders of thecentral nervous system (CNS) and the peripheral nervous system, e.g.,cognitive and neurodegenerative disorders, Examples of neurologicaldisorders include, but are not limited to, autonomic function disorderssuch as hypertension and sleep disorders, and neuropsychiatricdisorders, such as depression, schizophrenia, schizoaffective disorder,Korsakoff's psychosis, alcoholism, anxiety disorders, or phobicdisorders; learning or memory disorders, e.g., amnesia or age-relatedmemory loss, attention deficit disorder, dysthymic disorder, majordepressive disorder, mania, obsessive-compulsive disorder, psychoactivesubstance use disorders, anxiety, phobias, panic disorder, as well asbipolar affective disorder, e.g., severe bipolar affective (mood)disorder (BP-1), and bipolar affective neurological disorders, e.g.,migraine and obesity. Such neurological disorders include, for example,disorders involving neurons, and disorders involving glia, such asastrocytes, oligodendrocytes, ependymal cells, and microglia; cerebraledema, raised intracranial pressure and herniation, and hydrocephalus;malformations and developmental diseases, such as neural tube defects,forebrain anomalies, posterior fossa anomalies, and syringomyelia andhydromyelia; perinatal brain injury; cerebrovascular diseases, such asthose related to hypoxia, ischemia, and infarction, includinghypotension, hypoperfusion, and low-flow states—global cerebral ischemiaand focal cerebral ischemia—infarction from obstruction of local bloodsupply, intracranial hemorrhage, including intracerebral(intraparenchymal) hemorrhage, subarachnoid hemorrhage and rupturedberry aneurysms, and vascular malformations, hypertensivecerebrovascular disease, including lacunar infarcts, slit hemorrhages,and hypertensive encephalopathy; infections, such as acute meningitis,including acute pyogenic (bacterial) meningitis and acute aseptic(viral) meningitis, acute focal suppurative infections, including brainabscess, subdural empyema, and extradural abscess, chronic bacterialmeningoencephalitis, including tuberculosis and mycobacterioses,neurosyphilis, and neuroborreliosis (Lyme disease), viralmeningoencephalitis, including arthropod-borne (Arbo) viralencephalitis, Herpes simplex virus Type 1, Herpes simplex virus Type 2,Varicella-zoster virus (Herpes zoster), cytomegalovirus, poliomyelitis,rabies, and human immunodeficiency virus 1, including HIV-1meningoencephalitis (subacute encephalitis), vacuolar myelopathy,AIDS-associated myopathy, peripheral neuropathy, and AIDS in children,progressive multifocal leukoencephalopathy, subacute sclerosingpanencephalitis, fungal meningoencephalitis, other infectious diseasesof the nervous system; transmissible spongiform encephalopathies (priondiseases); demyelinating diseases, including multiple sclerosis,multiple sclerosis variants, acute disseminated encephalomyelitis andacute necrotizing hemorrhagic encephalomyelitis, and other diseases withdemyelination; degenerative diseases, such as degenerative diseasesaffecting the cerebral cortex, including Alzheimer's disease and Pick'sdisease, degenerative diseases of basal ganglia and brain stem,including Parkinsonism, idiopathic Parkinson's disease (paralysisagitans) and other Lewy diffuse body diseases, progressive supranuclearpalsy, corticobasal degenration, multiple system atrophy, includingstriatonigral degenration, Shy-Drager syndrome, and olivopontocerebellaratrophy, and Huntington's disease, senile dementia, Gilles de laTourette's syndrome, epilepsy, and Jakob-Creutzfieldt disease;spinocerebellar degenerations, including spinocerebellar ataxias,including Friedreich ataxia, and ataxia-telanglectasia, degenerativediseases affecting motor neurons, including amyotrophic lateralsclerosis (motor neuron disease), bulbospinal atrophy (Kennedysyndrome), and spinal muscular atrophy; inborn errors of metabolism,such as leukodystrophies, including Krabbe disease, metachromaticleukodystrophy, adrenoleukodystrophy, Pelizaeus-Merzbacher disease, andCanavan disease, mitochondrial encephalomyopathies, including Leighdisease and other mitochondrial encephalomyopathies; toxic and acquiredmetabolic diseases, including vitamin deficiencies such as thiamine(vitamin B₁) deficiency and vitamin B₁₂ deficiency, neurologic sequelaeof metabolic disturbances, including hypoglycemia, hyperglycemia, andhepatic encephatopathy, toxic disorders, including carbon monoxide,methanol, ethanol, and radiation, including combined methotrexate andradiation-induced injury; tumors, such as gliomas, includingastrocytoma, including fibrillary (diffuse) astrocytoma and glioblastomamultiforme, pilocytic astrocytoma, pleomorphic xanthoastrocytoma, andbrain stem glioma, oligodendroglioma, and ependymoma and relatedparaventricular mass lesions, neuronal tumors, poorly differentiatedneoplasms, including medulloblastoma, other parenchymal tumors,including primary brain lymphoma, germ cell tumors, and pinealparenchymal tumors, meningiomas, metastatic tumors, paraneoplasticsyndromes, peripheral nerve sheath tumors, including schwannoma,neurofibroma, and malignant peripheral nerve sheath tumor (malignantschwannoma), and neurocutaneous syndromes (phakomatoses), includingneurofibromotosis, including Type 1 neurofibromatosis (NF1) and TYPE 2neurofibromatosis (NF2), tuberous sclerosis, and Von Hippel-Lindaudisease. Further CNS-related disorders include, for example, thoselisted in the American Psychiatric Association's Diagnostic andStatistical manual of Mental Disorders (DSM), the most current versionof which is incorporated herein by reference in its entirety.

[0440] As used herein, diseases of the skin, include but are not limitedto, disorders of pigmentation and melanocytes, including but not limitedto, vitiligo, freckle, melasma, lentigo, nevocellular nevus, dysplasticnevi, and malignant melanoma; benign epithelial tumors, including butnot limited to, seborrheic keratoses, acanthosis nigricans,fibroepithelial polyp, epithelial cyst, keratoacanthoma, and adnexal(appendage) tumors; premalignant and malignant epidermal tumors,including but not limited to, actinic keratosis, squamous cellcarcinoma, basal cell carcinoma, and merkel cell carcinoma; tumors ofthe dermis, including but not limited to, benign fibrous histiocytoma,dermatofibrosarcoma protuberans, xanthomas, and dermal vascular tumors;tumors of cellular immigrants to the skin, including but not limited to,histiocytosis X, mycosis fungoides (cutaneous T-cell lymphoma), andmastocytosis; disorders of epidermal maturation, including but notlimited to, ichthyosis; acute inflammatory dermatoses, including but notlimited to, urticaria, acute eczematous dermatitis, and erythemamultiforme; chronic inflammatory dermatoses, including but not limitedto, psoriasis, lichen planus, and lupus erythematosus; blistering(bullous) diseases, including but not limited to, pemphigus, bullouspemphigoid, dermatitis herpetiformis, and noninflammatory blisteringdiseases: epidermolysis bullosa and porphyria; disorders of epidermalappendages, including but not limited to, acne vulgaris; panniculitis,including but not limited to, erythema nodosum and erythema induratum;and infection and infestation, such as verrucae, molluscum contagiosum,impetigo, superficial fungal infections, and arthropod bites, stings,and infestations.

[0441] Additionally, molecules of the invention can play an importantrole in the regulation of metabolism or pain disorders. Diseases ofmetabolic imbalance include, but are not limited to, obesity, anorexianervosa, cachexia, lipid disorders, and diabetes. Examples of paindisorders include, but are not limited to, pain response elicited duringvarious forms of tissue injury, e.g., inflammation, infection, andischemia, usually referred to as hyperalgesia (described in, forexample, Fields (1987) Pain, New York:McGraw-Hill); pain associated withmusculoskeletal disorders, e.g., joint pain; tooth pain; headaches; painassociated with surgery; pain related to irritable bowel syndrome; orchest pain.

[0442] As used herein, a “hematological disorder” includes a disease,disorder, or condition which affects a hematopoietic cell or tissue.Hematological disorders include diseases, disorders, or conditionsassociated with aberrant hematological content or function.Hematological disorders can be characterized by a misregulation (e.g.,downregulation or upregulation) of activity. Examples of hematologicaldisorders include disorders resulting from bone marrow irradiation orchemotherapy treatments for cancer, disorders such as Pernicious Anemia,Hemorrhagic Anemia, Hemolytic Anemia, Aplastic Anemia, Sickle CellAnemia, Sideroblastic Anemia, Anemia associated with chronic infectionssuch as Malaria, Trypanosomiasis, HIV, Hepatitis virus or other viruses,Myelophthisic Anemias caused by marrow deficiencies, renal failureresulting from Anemia, Anemia, Polycethemia, Infectious Mononucleosis(IM), Acute Non-Lymphocytic Leukemia (ANLL), Acute Myeloid Leukemia(AML), Acute Promyelocytic Leukemia (APL), Acute Myelomonocytic Leukemia(AMMoL), Polycethemia Vera, Lymphoma, Acute Lymphocytic Leukemia (ALL),Chronic Lymphocytic Leukemia, Wilm's Tumor, Ewing's Sarcoma,Retinoblastoma, Hemophilia, disorders associated with an increased riskof Thrombosis, Herpes, Thalessemia, antibody-mediated disorders such astransfusion reactions and Erythroblastosis, mechanical trauma to redblood cells such as micro-angiopathic hemolytic anemias, ThromboticThrombocytopenic Purpura and disseminated intravascular coagulation,infections by parasites such as Plasmodium, chemical injuries from,e.g., lead poisoning, and Hypersplenism.

[0443] As used herein, the term “hematopoietic cell” includes yolk sacstem cells, primitive erythroid cells, fetal liver cells, fetal spleencells, fetal bone marrow cells, non-fetal bone marrow cells,megakaryocytes, stem cells, lymphoid stem cells, myeloid stem cells,progenitor cells, progenitor lymphocytes, progenitor T lymphocytes,progenitor B lymphocytes, progenitor erythrocytes, progenitorneutrophils, progenitor eosinophils, progenitor basophils, progenitormonocytes, progenitor mast cells, progenitor platelets, committedlymphocytes, committed T lymphocytes, committed B lymphocytes, committederythrocytes, committed neutrophils, committed eosinophils, committedbasophils, committed monocytes, committed mast cells, committedplatelets, differentiated lymphocytes, differentiated T lymphocytes,differentiated B lymphocytes, differentiated erythrocytes,differentiated neutrophils, differentiated eosinophils, differentiatedbasophils, differentiated monocytes, differentiated mast cells,differentiated platelets, mature lymphocytes, mature T lymphocytes,mature B lymphocytes, mature erythrocytes, mature neutrophils, matureeosinophils, mature basophils, mature monocytes, mature mast cells, andmature platelets.

[0444] As used herein, the term “progenitor cell” includes any somaticcell which has the capacity to generate fully differentiated, functionalprogeny by differentiation and proliferation. Progenitor cells includeprogenitors from any tissue or organ system, including, but not limitedto, blood, nerve, muscle, skin, gut, bone, kidney, liver, pancreas,thymus, and the like. Progenitor cells are distinguished from “committedcells” and “differentiated cells,” which are defined as those cellswhich may or may not have the capacity to proliferate, i.e.,self-replicate, but which are unable to undergo further differentiationto a different cell type under normal physiological conditions.Moreover, progenitor cells are further distinguished from abnormal cellssuch as cancer cells, especially leukemia cells, which proliferate(self-replicate) but which generally do not further differentiate,despite appearing to be immature or undifferentiated.

[0445] Progenitor cells include all the cells in a lineage ofdifferentiation and proliferation prior to the most differentiated orthe fully mature cell. Thus, for example, progenitors include the skinprogenitor in the mature individual, which is capable of differentiationto only one type of cell, but which is itself not fully mature or fullydifferentiated. Production of mature, functional blood cells resultsfrom proliferation and differentiation of “unipotential progenitors,”i.e., those progenitors which have the capacity to make only one type ofone type of blood cell. For red blood cell production, a progenitorcalled a “CFU-E” (colony forming unit-erythroid) has the capacity togenerate two to 32 progeny cells.

[0446] Various other hematopoietic progenitors have been characterized.For example, hematopoietic progenitor cells include those cells whichare capable of successive cycles of differentiating and proliferating toyield up to eight different mature hematopoietic cell lineages. At themost primitive or undifferentiated end of the hematopoietic spectrum,hematopoietic progenitor cells include the hematopoietic “stem cells.”These rare cells, which represent 1 in 10,000 to 1 in 100,000 of cellsin the bone marrow, each have the capacity to generate a billion matureblood cells of all lineages and are responsible for sustaining bloodcell production over the life of an animal. They reside in the marrowprimarily in a quiescent state and may form identical daughter cellsthrough a process called self-renewal. Accordingly, such an uncommittedprogenitor can be described as being “totipotent,” i.e., both necessaryand sufficient for generating all types of mature blood cells.Progenitor cells which retain a capacity to generate all blood celllineages but which can not self-renew are termed “pluripotent.” Cellswhich can produce some but not all blood lineages and can not self-reneware termed “multipotent.”

[0447] As used herein, “hematopoietic cell activity” includes anactivity exerted by a hematopoietic cell, or an activity that takesplace in a hematopoietic cell. For example, such activities includecellular processes that contribute to the physiological role ofhematopoietic cells, such as hematopoiesis, but are not limited to, cellproliferation, differentiation, growth, migration and programmed celldeath.

[0448] As used herein, the term “erythroid associated disorders” includedisorders involving aberrant (increased or deficient) erythroblastproliferation, e.g., an erythroleukemia, and aberrant (increased ordeficient) erythroblast differentiation, e.g., an anemia.Erythrocyte-associated disorders include anemias such as, for example,drug (chemotherapy-) induced anemias, hemolytic anemias due tohereditary cell membrane abnormalities, such as hereditaryspherocytosis, hereditary elliptocytosis, and hereditarypyropoikilocytosis; hemolytic anemias due to acquired cell membranedefects, such as paroxysmal nocturnal hemoglobinuria and spur cellanemia; hemolytic anemias caused by antibody reactions, for example tothe RBC antigens, or antigens of the ABO system, Lewis system, Iisystem, Rh system, Kidd system, Duffy system, and Kell system;methemoglobinemia; a failure of erythropoiesis, for example, as a resultof aplastic anemia, pure red cell aplasia, myelodysplastic syndromes,sideroblastic anemias, and congenital dyserythropoietic anemia;secondary anemia in non-hematolic disorders, for example, as a result ofchemotherapy, alcoholism, or liver disease; anemia of chronic disease,such as chronic renal failure; and endocrine deficiency diseases.

[0449] Anemias are an important class of disorders which affecterythroid cell growth or differentiation. Anemias include a variety ofdisorders in which the content of erythrocytes or hemoglobin in theblood is insufficient to fully provide transportation of oxygen for allof the body's needs. Examples of anemias include hemolytic anemiasattributable to hereditary cell membrane abnormalities (e.g., hereditaryspherocytosis, hereditary elliptocytosis, and hereditarypyropoikilocytosis), hemolytic anemias attributable to acquired cellmembrane defects (e.g., paroxysmal nocturnal hemoglobinuria and spurcell anemia), hemolytic anemias attributable to antibody reactions(e.g., reactions to RBC antigens or antigens of the ABO system, Lewissystem, Ii system, Rh system, Kidd system, Duffy system, and Kellsystem), methemoglobinemia, anemias attributable to a failure oferythropoiesis (e.g., as a result of aplastic anemia, pure red cellaplasia, myelodysplastic syndromes, sideroblastic anemias, or congenitaldyserythropoietic anemia), secondary anemia in non-hematologicaldisorders (e.g., anemia attributable to chemotherapy, alcoholism, orliver disease), anemia associated with a chronic disease (e.g., anemiaassociated with chronic renal failure), anemias attributable tobleeding, and anemia associated with endocrine deficiency diseases. Someof these disorders are known to affect growth or differentiation oferythroid cells.

[0450] As used herein, the term “modulate” includes alteration of, e.g.,by increasing or decreasing the particular parameter being described.

[0451] As used herein, the term “apoptosis” includes programmed celldeath which can be characterized using techniques which are known in theart. Apoptotic cell death can be characterized, e.g., by cell shrinkage,membrane blebbing and chromatin condensation culminating in cellfragmentation. Cells undergoing apoptosis also display a characteristicpattern of internucleosomal DNA cleavage.

[0452] As used herein, the term “endocrine disorder” includes, but isnot limited to, disorders of the pancreas, e.g., diabetes mellitus;islet cell tumors, including but not limited to, insulinomas,gastrinomas, and other rare islet cell tumors, the pituitary, or thehypothalamus.

[0453] Various aspects of the invention are described in further detailbelow.

[0454] Isolated Nucleic Acid Molecules

[0455] In one aspect, the invention provides, an isolated or purified,nucleic acid molecule that encodes a 27877, 18080, 14081, 32140, 50352,16658, 14223, 16002, 50566, 65552 or 65577 polypeptide described herein,e.g., a full length 27877, 18080, 14081, 32140, 50352, 16658, 14223,16002, 50566, 65552 or 65577 protein or a fragment thereof, e.g., abiologically active portion of 27877, 18080, 14081, 32140, 50352, 16658,14223, 16002, 50566, 65552 or 65577 protein. Also included is a nucleicacid fragment suitable for use as a hybridization probe, which can beused, e.g., to identify a nucleic acid molecule encoding a polypeptideof the invention, 27877, 18080, 14081, 32140, 50352, 16658, 14223,16002, 50566, 65552 or 65577 mRNA, and fragments suitable for use asprimers, e.g., PCR primers for the amplification or mutation of nucleicacid molecules.

[0456] In one embodiment, an isolated nucleic acid molecule of theinvention includes the nucleotide sequence shown in SEQ ID NO: 1, 3, 4,6, 11, 13, 20, 22, 25, 27, 29, 31, 35, 37, 38, 40, 41, 43, 73, 75, 76,78, 86 or 88, or a portion of any of this nucleotide sequence. In oneembodiment, the nucleic acid molecule includes sequences encoding thehuman. 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566,65552 or 65577 protein (i.e., “the coding region” of SEQ ID NO: 1, 4,11, 20, 25, 29, 35, 38, 41, 73, 76 or 86, as shown in SEQ ID NO: 3, 6,13, 22, 27, 31, 37, 40, 43, 75, 78 or 88, respectively), as well as 5′untranslated sequences and 3′ untranslated sequences. Alternatively, thenucleic acid molecule can include only the coding region of SEQ ID NO:1, 4, 11, 20, 25, 29, 35, 38, 41, 73, 76 or 86 (e.g., SEQ ID NO: 3, 6,13, 22, 27, 31, 37, 40, 43, 75, 78 or 88) and, e.g., no flankingsequences which normally accompany the subject sequence. In anotherembodiment, the nucleic acid molecule encodes a sequence correspondingto a fragment of the protein corresponding to conserved domainsidentified within SEQ ID NO: 2, 5, 12, 21, 26, 30, 36, 39, 42, 74, 77 or87.

[0457] In another embodiment, an isolated nucleic acid molecule of theinvention includes a nucleic acid molecule which is a complement of thenucleotide sequence shown in SEQ ID NO: 1, 3, 4, 6, 11, 13, 20, 22, 25,27, 29, 31, 35, 37, 38, 40, 41, 43, 73, 75, 76, 78, 86 or 88, or aportion of any of these nucleotide sequences. In other embodiments, thenucleic acid molecule of the invention is sufficiently complementary tothe nucleotide sequence shown in SEQ ID NO: 1, 3, 4, 6, 11, 13, 20, 22,25, 27, 29, 31, 35, 37, 38, 40, 41, 43, 73, 75, 76, 78, 86 or 88 suchthat it can hybridize to the nucleotide sequence shown in SEQ ID NO: 1,3, 4, 6, 11, 13, 20, 22, 25, 27, 29, 31, 35, 37, 38, 40, 41, 43, 73, 75,76, 78, 86 or 88, thereby forming a stable duplex.

[0458] In one embodiment, an isolated nucleic acid molecule of thepresent invention includes a nucleotide sequence which is at leastabout: 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%,97%, 98%, 99%, or more homologous to the entire length of the nucleotidesequence shown in SEQ ID NO: 1, 3, 4, 6, 11, 13, 20, 22, 25, 27, 29, 31,35, 37, 38, 40, 41, 43, 73, 75, 76, 78, 86 or 88, or a portion,preferably of the same length, of any of these nucleotide sequences.

[0459] 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566,65552 or 65577 Nucleic Acid Fragments

[0460] A nucleic acid molecule of the invention can include only aportion of the nucleic acid sequence of SEQ ID NO: 1, 3, 4, 6, 11, 13,20, 22, 25, 27, 29, 31, 35, 37, 38, 40, 41, 43, 73, 75, 76, 78, 86 or88. For example, such a nucleic acid molecule can include a fragmentwhich can be used as a probe or primer or a fragment encoding a portionof a 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566,65552 or 65577 protein, e.g., an immunogenic. or biologically activeportion of a 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577 protein. A fragment can comprise those nucleotidesof SEQ ID NO: 1, 3, 4, 6, 11, 13, 20, 22, 25, 27, 29, 31, 35, 37, 38,40, 41, 43, 73, 75, 76, 78, 86 or 88, which encode a domain of human27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or65577. The nucleotide sequence determined from the cloning of the 27877,18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577gene allows for the generation of probes and primers designed for use inidentifying and/or cloning other 27877, 18080, 14081, 32140, 50352,16658, 14223, 16002, 50566, 65552 or 65577 family members, or fragmentsthereof, as well as 27877, 18080, 14081, 32140, 50352, 16658, 14223,16002, 50566, 65552 or 65577 homologs, or fragments thereof, from otherspecies.

[0461] In another embodiment, a nucleic acid includes a nucleotidesequence that includes part, or all, of the coding region and extendsinto either (or both) the 5′ or 3′ noncoding region. Other embodimentsinclude a fragment which includes a nucleotide sequence encoding anamino acid fragment described herein. Nucleic acid fragments can encodea specific domain or site described herein or fragments thereof,particularly fragments thereof which are at least 100 amino acids inlength. Fragments also include nucleic acid sequences corresponding tospecific amino acid sequences described above or fragments thereof.Nucleic acid fragments should not to be construed as encompassing thosefragments that may have been disclosed prior to the invention.

[0462] A nucleic acid fragment can include a sequence corresponding to adomain, region, or functional site described herein. A nucleic acidfragment can also include one or more domain, region, or functional sitedescribed herein. Thus, for example, a 27877, 18080, 14081, 32140,50352, 16658, 14223, 16002, 50566, 65552 or 65577 nucleic acid fragmentcan include a sequence corresponding to a domain of 27877, 18080, 14081,32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577, as describedherein.

[0463] 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566,65552 or 65577 probes and primers are provided. Typically a probe/primeris an isolated or purified oligonucleotide. The oligonucleotidetypically includes a region of nucleotide sequence that hybridizes understringent conditions to at least about 7, 12 or 15, preferably about 20or 25, more preferably about 30, 35, 40, 45, 50, 55, 60, 65, or 75consecutive nucleotides of a sense or antisense sequence of SEQ ID NO:1, 3, 4, 6, 11, 13, 20, 22, 25, 27, 29, 31, 35, 37, 38, 40, 41, 43, 73,75, 76, 78, 86 or 88, or of a naturally occurring allelic variant ormutant of SEQ ID NO: 1, 3, 4, 6, 11, 13, 20, 22, 25, 27, 29, 31, 35, 37,38, 40, 41, 43, 73, 75, 76, 78, 86 or 88.

[0464] In a preferred embodiment the nucleic acid is a probe which is atleast 5 or 10, and less than 200, more preferably less than 100, or lessthan 50, base pairs in length. It should be identical, or differ by 1,or less than in 5 or 10 bases, from a sequence disclosed herein. Ifalignment is needed for this comparison the sequences should be alignedfor maximum homology. “Looped” out sequences from deletions orinsertions, or mismatches, are considered differences.

[0465] A probe or primer can be derived from the sense or anti-sensestrand of a nucleic acid which encodes a domain identified in the 27877,18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577sequences.

[0466] In another embodiment a set of primers is provided, e.g., primerssuitable for use in a PCR, which can be used to amplify a selectedregion of a 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577 sequence, e.g., a domain, region, site or othersequence described herein. The primers should be at least 5, 10, or 50base pairs in length and less than 100, or less than 200, base pairs inlength. The primers should be identical, or differ by one base from asequence disclosed herein or from a naturally occurring variant.

[0467] A nucleic acid fragment can encode an epitope bearing region of apolypeptide described herein.

[0468] A nucleic acid fragment encoding a “biologically active portionof a 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566,65552 or 65577 polypeptide” can be prepared by isolating a portion ofthe nucleotide sequence of SEQ ID NO: 1, 3, 4, 6, 11, 13, 20, 22, 25,27, 29, 31, 35, 37, 38, 40, 41, 43, 73, 75, 76, 78, 86 or 88, whichencodes a polypeptide having a 27877, 18080, 14081, 32140, 50352, 16658,14223, 16002, 50566, 65552 or 65577 biological activity (e.g., thebiological activities of the 27877, 18080, 14081, 32140, 50352, 16658,14223, 16002, 50566, 65552 or 65577 proteins are described herein),expressing the encoded portion of the 27877, 18080, 14081, 32140, 50352,16658, 14223, 16002, 50566, 65552 or 65577 protein (e.g., by recombinantexpression in vitro) and assessing the activity of the encoded portionof the 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566,65552 or 65577 protein. A nucleic acid fragment encoding a biologicallyactive portion of a 27877, 18080, 14081, 32140, 50352, 16658, 14223,16002, 50566, 65552 or 65577 polypeptide, can comprise a nucleotidesequence which is greater than 300 or more nucleotides in length.

[0469] In preferred embodiments, a nucleic acid includes a nucleotidesequence which is about 300, 400, 500, 600, 700, 800, 900, 1000, 1100,1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300,2400, 2500, 2600, 2700, 2800, 2900, 3000, 3100, 3200, 3300, 3400, 3500,3600, 3700, 3800, 3900, 4000, 4100, 4200, 4300, 4400, 4500, 4600, 4700,4800, 4900, 5000, 5100, 5200, 5300, 5400, 5500, 5600, 5700, 5800, 5900,6000, 6100, 6200, 6300, 6400, 6500, 6600, 6700, 6800, 6900, 7000, 7100,7200, or more nucleotides in length and hybridizes under stringenthybridization conditions to a nucleic acid molecule of SEQ ID NO: 1, 3,4, 6, 11, 13, 20, 22, 25, 27, 29, 31, 35, 37, 38, 40, 41, 43, 73, 75,76, 78, 86 or 88.

[0470] 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566,65552 or 65577 Nucleic Acid Variants

[0471] The invention further encompasses nucleic acid molecules thatdiffer from the nucleotide sequence shown in SEQ ID NO: 1, 3, 4, 6, 11,13, 20, 22, 25, 27, 29, 31, 35, 37, 38, 40, 41, 43, 73, 75, 76, 78, 86or 88. Such differences can be due to degeneracy of the genetic code(and result in a nucleic acid which encodes the same 27877, 18080,14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 proteinsas those encoded by the nucleotide sequence disclosed herein. In anotherembodiment, an isolated nucleic acid molecule of the invention has anucleotide sequence encoding a protein having an amino acid sequencewhich differs, by at least 1, but less than 5, 10, 20, 50, or 100 aminoacid residues that shown in SEQ ID NO: 2, 5, 12, 21, 26, 30, 36, 39, 42,74, 77 or 87. If alignment is needed for this comparison the sequencesshould be aligned for maximum homology. “Looped” out sequences fromdeletions or insertions, or mismatches, are considered differences.

[0472] Nucleic acids of the inventor can be chosen for having codons,which are preferred, or non-preferred, for a particular expressionsystem. E.g., the nucleic acid can be one in which at least one codon,at preferably at least 10%, or 20% of the codons has been altered suchthat the sequence is optimized for expression in E. coli, yeast, human,insect, or CHO cells.

[0473] Nucleic acid variants can be naturally occurring, such as allelicvariants (same locus), homologs (different locus), and orthologs(different organism) or can be non naturally occurring. Non-naturallyoccurring variants can be made by mutagenesis techniques, includingthose applied to polynucleotides, cells, or organisms. The variants cancontain nucleotide substitutions, deletions, inversions and insertions.Variation can occur in either or both the coding and non-coding regions.The variations can produce both conservative and non-conservative aminoacid substitutions (as compared in the encoded product).

[0474] In a preferred embodiment, the nucleic acid differs from that ofSEQ ID NO: 1, 3, 4, 6, 11, 13, 20, 22, 25, 27, 29, 31, 35, 37,38,40,41,43, 73, 75, 76, 78, 86 or 88, e.g., as follows: by at least onebut less than 10, 20, 30, or 40 nucleotides; at least one but less than1%, 5%, 10% or 20% of the nucleotides in the subject nucleic acid. Ifnecessary for this analysis the sequences should be aligned for maximumhomology. “Looped” out sequences from deletions or insertions, ormismatches, are considered differences.

[0475] Orthologs, homologs, and allelic variants can be identified usingmethods known in the art. These variants comprise a nucleotide sequenceencoding a polypeptide that is 50%, at least about 55%, typically atleast about 70-75%, more typically at least about 80-85%, and mosttypically at least about 90-95% or more identical to the nucleotidesequence shown in SEQ ID NO: 2, 5, 12, 21, 26, 30, 36, 39, 42, 74, 77 or87 or a fragment of this sequence. Such nucleic acid molecules canreadily be identified as being able to hybridize under stringentconditions, to the nucleotide sequence shown in SEQ ID NO: 2, 5, 12, 21,26, 30, 36, 39, 42, 74, 77 or 87 or a fragment of the sequence. Nucleicacid molecules corresponding to orthologs, homologs, and allelicvariants of the 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577 cDNAs of the invention can further be isolated bymapping to the same chromosome or locus as the 27877, 18080, 14081,32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 gene. Preferredvariants include those that are correlated with activities specific tothe molecules of the invention, i.e. phospholipase activity, serinecarboxypeptidase activity, trypsin-like serine protease activity,aldehyde dehydrogenase activity, ubiquitin-protein ligase activity,protein kinase activity, hydrolase activity or matrix metalloproteinaseactivity.

[0476] Allelic variants of 27877, 18080, 14081, 32140, 50352, 16658,14223, 16002, 50566, 65552 or 65577, e.g., human 27877, 18080, 14081,32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577, include bothfunctional and non-functional proteins. Functional allelic variants arenaturally occurring amino acid sequence variants of the 27877, 18080,14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 proteinwithin a population that maintain the ability to bind a 27877, 18080,14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 ligandor substrate and/or modulate phospholipase activity, serinecarboxypeptidase activity, trypsin-like serine protease activity,aldehyde dehydrogenase activity, ubiquitin-protein ligase activity,protein kinase activity, hydrolase activity or matrix metalloproteinaseactivity. Functional allelic variants will typically contain onlyconservative substitution of one or more amino acids of SEQ ID NO: 2, 5,12, 21, 26, 30, 36, 39, 42, 74, 77 or 87, or substitution, deletion orinsertion of non-critical residues in non-critical regions of theprotein. Non-functional allelic variants are naturally-occurring aminoacid sequence variants of the 27877, 18080, 14081, 32140, 50352, 16658,14223, 16002, 50566, 65552 or 65577, e.g., human 27877, 18080, 14081,32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577, protein withina population that do not have the ability to bind a 27877, 18080, 14081,32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 ligand orsubstrate and/or phospholipase activity, serine carboxypeptidaseactivity, trypsin-like serine protease activity, aldehyde dehydrogenaseactivity, ubiquitin-protein ligase activity, protein kinase activity,hydrolase activity or matrix metalloproteinase activity. Non-functionalallelic variants will typically contain a non-conservative substitution,a deletion, or insertion, or premature truncation of the amino acidsequence of SEQ ID NO: 2, 5, 12, 21, 26, 30, 36, 39, 42, 74, 77 or 87,or a substitution, insertion, or deletion in critical residues orcritical regions of the protein.

[0477] Moreover, nucleic acid molecules encoding other 27877, 18080,14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 familymembers and, thus, which have a nucleotide sequence which differs fromthe 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552or 65577 sequences of SEQ ID NO: 1, 3, 4, 6, 11, 13, 20, 22, 25, 27, 29,31, 35, 37, 38, 40, 41, 43, 73, 75, 76, 78, 86 or 88 are intended to bewithin the scope of the invention.

[0478] Antisense Nucleic Acid Molecules, Ribozymes and Modified 27877,18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577Nucleic Acid Molecules

[0479] In another aspect, the invention features, an isolated nucleicacid molecule which is antisense to 27877, 18080, 14081, 32140, 50352,16658, 14223, 16002, 50566, 65552 or 65577. An “antisense” nucleic acidcan include a nucleotide sequence which is complementary to a “sense”nucleic acid encoding a protein, e.g., complementary to the codingstrand of a double-stranded cDNA molecule or complementary to an mRNAsequence. The antisense nucleic acid can be complementary to an entire27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or65577 coding strand, or to only a portion thereof (e.g., the codingregion of human 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577 corresponding to SEQ ID NO: 3, 6, 13, 22, 27, 31,37, 40, 43, 75, 78, 88, respectively). In another embodiment, theantisense nucleic acid molecule is antisense to a “noncoding region” ofthe coding strand of a nucleotide sequence encoding 27877, 18080, 14081,32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 (e.g., the 5′and 3′ untranslated regions).

[0480] An antisense nucleic acid can be designed such that it iscomplementary to the entire coding region of 27877, 18080, 14081, 32140,50352, 16658, 14223, 16002, 50566, 65552 or 65577 mRNA, but morepreferably is an oligonucleotide which is antisense to only a portion ofthe coding or noncoding region of 27877, 18080, 14081, 32140, 50352,16658, 14223, 16002, 50566, 65552 or 65577 mRNA. For example, theantisense oligonucleotide can be complementary to the region surroundingthe translation start site of 27877, 18080, 14081, 32140, 50352, 16658,14223, 16002, 50566, 65552 or 65577 mRNA, e.g., between the −10 and +10regions of the target gene nucleotide sequence of interest. An antisenseoligonucleotide can be, for example, about 7, 10, 15, 20, 25, 30, 35,40, 45, 50, 55, 60, 65, 70, 75, 80, or more nucleotides in length.

[0481] An antisense nucleic acid of the invention can be constructedusing chemical synthesis and enzymatic ligation reactions usingprocedures known in the art. For example, an antisense nucleic acid(e.g., an antisense oligonucleotide) can be chemically synthesized usingnaturally occurring nucleotides or variously modified nucleotidesdesigned to increase the biological stability of the molecules or toincrease the physical stability of the duplex formed between theantisense and sense nucleic acids, e.g., phosphorothioate derivativesand acridine substituted nucleotides can be used. The antisense nucleicacid also can be produced biologically using an expression vector intowhich a nucleic acid has been subcloned in an antisense orientation(i.e., RNA transcribed from the inserted nucleic acid will be of anantisense orientation to a target nucleic acid of interest, describedfurther in the following subsection).

[0482] The antisense nucleic acid molecules of the invention aretypically administered to a subject (e.g., by direct injection at atissue site), or generated in situ such that they hybridize with or bindto cellular mRNA and/or genomic DNA encoding a 27877, 18080, 14081,32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 protein tothereby inhibit expression of the protein, e.g., by inhibitingtranscription and/or translation. Alternatively, antisense nucleic acidmolecules can be modified to target selected cells and then administeredsystemically. For systemic administration, antisense molecules can bemodified such that they specifically or selectively bind to receptors orantigens expressed on a selected cell surface, e.g., by linking theantisense nucleic acid molecules to peptides or antibodies which bind tocell surface receptors or antigens. The antisense nucleic acid moleculescan also be delivered to cells using the vectors described herein. Toachieve sufficient intracellular concentrations of the antisensemolecules, vector constructs in which the antisense nucleic acidmolecule is placed under the control of a strong pol II or pol IIIpromoter are preferred.

[0483] In yet another embodiment, the antisense nucleic acid molecule ofthe invention is an α-anomeric nucleic acid molecule. An α-anomericnucleic acid molecule forms specific double-stranded hybrids withcomplementary RNA in which, contrary to the usual β-units, the strandsrun parallel to each other (Gaultier et al. (1987) Nucleic Acids. Res.15:6625-6641). The antisense nucleic acid molecule can also comprise a2′-o-methylribonucleotide (Inoue et al. (1987) Nucleic Acids Res.15:6131-6148) or a chimeric RNA-DNA analogue (Inoue et al. (1987) FEBSLett. 215:327-330).

[0484] In still another embodiment, an antisense nucleic acid of theinvention is a ribozyme. A ribozyme having specificity for a 27877,18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or65577-encoding nucleic acid can include one or more sequencescomplementary to the nucleotide sequence of a 27877, 18080, 14081,32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 cDNA disclosedherein (i.e., SEQ ID NO: 1, 3, 4, 6, 11, 13, 20, 22, 25, 27, 29, 31, 35,37, 38, 40, 41, 43, 73, 75, 76, 78, 86or 88), and a sequence havingknown catalytic sequence responsible for mRNA cleavage (see U.S. Pat.No. 5,093,246 or Haselhoff and Gerlach (1988) Nature 334:585-591). Forexample, a derivative of a Tetrahymena L-19 IVS RNA can be constructedin which the nucleotide sequence of the active site is complementary tothe nucleotide sequence to be cleaved in a 27877, 18080, 14081, 32140,50352, 16658, 14223, 16002, 50566, 65552 or 65577-encoding mRNA. See,e.g., Cech et al. U.S. Pat. No. 4,987,071; and Cech et al. U.S. Pat. No.5,116,742. Alternatively, 27877, 18080, 14081, 32140, 50352, 16658,14223, 16002, 50566, 65552 or 65577 mRNA can be used to select acatalytic RNA having a specific ribonuclease activity from a pool of RNAmolecules. See, e.g., Bartel and Szostak (1993) Science 261:1411-1418.

[0485] 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566,65552 or 65577 gene expression can be inhibited by targeting nucleotidesequences complementary to the regulatory region of the 27877, 18080,14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 (e.g.,the 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552or 65577 promoter and/or enhancers) to form triple helical structuresthat prevent transcription of the 27877, 18080, 14081, 32140, 50352,16658, 14223, 16002, 50566, 65552 or 65577 gene in target cells. Seegenerally, Helene (1991) Anticancer Drug Des. 6:569-84; Helene (1992)Ann. N.Y. Acad. Sci. 660:27-36; and Maher (1992) Bioassays 14:807-15.The potential sequences that can be targeted for triple helix formationcan be increased by creating a so-called “switchback” nucleic acidmolecule. Switchback molecules are synthesized in an alternating 5′-3′,3′-5′ manner, such that they base pair with first one strand of a duplexand then the other, eliminating the necessity for a sizeable stretch ofeither purines or pyrimidines to be present on one strand of a duplex.

[0486] The invention also provides detectably labeled oligonucleotideprimer and probe molecules. Typically, such labels are chemiluminescent,fluorescent, radioactive, or colorimetric.

[0487] A 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566,65552 or 65577 nucleic acid molecule can be modified at the base moiety,sugar moiety or phosphate backbone to improve, e.g., the stability,hybridization, or solubility of the molecule. For example, thedeoxyribose phosphate backbone of the nucleic acid molecules can bemodified to generate peptide nucleic acids (see Hyrup et al. (1996)Bioorganic & Medicinal Chemistry 4: 5-23).

[0488] As used herein, the terms “peptide nucleic acid” or “PNA” refersto a nucleic acid mimic, e.g., a DNA mimic, in which the deoxyribosephosphate backbone is replaced by a pseudopeptide backbone and only thefour natural nucleobases are retained. The neutral backbone of a PNA canallow for specific hybridization to DNA and RNA under conditions of lowionic strength. The synthesis of PNA oligomers can be performed usingstandard solid phase peptide synthesis protocols as described in Hyrupet al. (1996) supra; Perry-O'Keefe et al. (1996) Proc. Natl. Acad. Sci.93: 14670-675.

[0489] PNAs of 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577 nucleic acid molecules can be used in therapeuticand diagnostic applications. For example, PNAs can be used as antisenseor antigene agents for sequence-specific modulation of gene expressionby, for example, inducing transcription or translation arrest orinhibiting replication. PNAs of 27877, 18080, 14081, 32140, 50352,16658, 14223, 16002, 50566, 65552 or 65577 nucleic acid molecules canalso be used in the analysis of single base pair mutations in a gene,(e.g., by PNA-directed PCR clamping); as ‘artificial restrictionenzymes’ when used in combination with other enzymes, (e.g., S1nucleases (Hyrup et al. (1996) supra)); or as probes or primers for DNAsequencing or hybridization (Hyrup et al. (1996) supra; Perry-O'Keefesupra).

[0490] In other embodiments, the oligonucleotide can include otherappended groups such as peptides (e.g., for targeting host cellreceptors in vivo), or agents facilitating transport across the cellmembrane (see, e.g., Letsinger et al. (1989) Proc. Natl Acad. Sci USA86:6553-6556; Lemaitre et al. (1987) Proc. Natl. Acad. Sci. USA84:648-652; PCT Publication No. W088/09810) or the blood-brain barrier(see, e.g., PCT Publication No. W089/10134). In addition,oligonucleotides can be modified with hybridization-triggered cleavageagents (see, e.g., Krol et al. (1988) Bio-Techniques 6:958-976) orintercalating agents. (see, e.g., Zon (1988) Pharm. Res. 5:539-549). Tothis end, the oligonucleotide can be conjugated to another molecule,(e.g., a peptide, hybridization triggered cross-linking agent, transportagent, or hybridization-triggered cleavage agent).

[0491] The invention also includes molecular beacon oligonucleotideprimer and probe molecules having at least one region which iscomplementary to a 27877, 18080, 14081, 32140, 50352, 16658, 14223,16002, 50566, 65552 or 65577 nucleic acid of the invention, twocomplementary regions one having a fluorophore and one a quencher suchthat the molecular beacon is useful for quantitating the presence of the27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or65577 nucleic acid of the invention in a sample. Molecular beaconnucleic acids are described, for example, in Lizardi et al., U.S. Pat.No. 5,854,033; Nazarenko et al., U.S. Pat. No. 5,866,336, and Livak etal., U.S. Pat. No. 5,876,930.

[0492] Isolated 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577 Polypeptides

[0493] In another aspect, the invention features, an isolated 27877,18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577protein, or fragment, e.g., a biologically active portion, for use asimmunogens or antigens to raise or test (or more generally to bind)anti-27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566,65552 or 65577 antibodies. 27877, 18080, 14081, 32140, 50352, 16658,14223, 16002, 50566, 65552 or 65577 protein can be isolated from cellsor tissue sources using standard protein purification techniques. 27877,18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577protein or fragments thereof can be produced by recombinant DNAtechniques or synthesized chemically.

[0494] Polypeptides of the invention include those which arise as aresult of the existence of multiple genes, alternative transcriptionevents, alternative RNA splicing events, and alternative translationaland post-translational events. The polypeptide can be expressed insystems, e.g., cultured cells, which result in substantially the samepost-translational modifications present when the polypeptide isexpressed in a native cell, or in systems which result in the alterationor omission of post-translational modifications, e.g., glycosylation orcleavage, present in a native cell.

[0495] In a preferred embodiment, a 27877, 18080, 14081, 32140, 50352,16658, 14223, 16002, 50566, 65552 or 65577 polypeptide has one or moreof the following characteristics:

[0496] it has the ability to catalyze the hydrolysis of an acyl orphosphoacyl bond of a phospholipids; to modulate removal ofCOOH-terminal residues; (ii) it has the ability to modulate the transferof an acyl group from a donor to an acceptor molecule; (iii) it has theability to phosphorylate carbohydrates; (iv) it has the ability tooxidate an aldehyde; (v) it has the ability to modulate ubiquitinationof a substrate; (vi) it has the ability to reversibly phosphorylateproteins in order to regulate protein activity in eukaryotic cells;(vii) it has the ability to interact with cytotoxins and metabolites;(viii) it has the ability to catalyze the metabolism of a cytotoxin ormetabolite; (ix) it has the ability to hydrolyze a thioester containingcompound; (x) it has the ability to catalyze the formation of athioester conjugation on a substrate; (xi) it has the ability to cleaveor modulate the degradation of proteins or peptides of the extracellularmatrix; (xii) it has the ability to catalyze or modulate catalysis ofcleavage of covalent bonds within or between amino acid residues; (xiii)it has a molecular weight, e.g., a deduced molecular weight, preferablyignoring any contribution of post translational modifications, aminoacid composition or other physical characteristic of a 27877, 18080,14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577polypeptide, e.g., a polypeptide of SEQ ID NO: 2, 5, 12, 21, 26, 30, 36,39, 42, 74, 77 or 87; (xiv) it has an overall sequence similarity of atleast 60%, preferably at least 70%, more preferably at least 80, 90, or95%, with a polypeptide of SEQ ID NO: 2, 5, 12, 21, 26, 30, 36, 39, 42,74, 77 or 87; (xv) it is expressed in a multitude of human tissues andcell lines (refer to section for each molecule of the invention); and ithas specific domains which are preferably about 70%, 80%, 90% or 95%identical to the identified amino acid residues of SEQ ID NO: 2, 5, 12,21, 26, 30, 36, 39, 42, 74, 77 or 87 (refer to section for each moleculeof the invention for domain names and locations within amino acidsequence).

[0497] In a preferred embodiment the 27877, 18080, 14081, 32140, 50352,16658, 14223, 16002, 50566, 65552 or 65577 protein, or fragment thereof,differs from the corresponding sequence in SEQ ID NO: 2, 5, 12, 21, 26,30, 36, 39, 42, 74, 77 or 87. In one embodiment it differs by at leastone but by less than 15, 10 or 5 amino acid residues. In another itdiffers from the corresponding sequence in SEQ ID NO: 2, 5, 12, 21, 26,30, 36, 39, 42, 74, 77 or 87 by at least one residue but less than 20%,15%, 10% or 5% of the residues in it differ from the correspondingsequence in SEQ ID NO: 2, 5, 12, 21, 26, 30, 36, 39, 42, 74, 77 or 87.(If this comparison requires alignment the sequences should be alignedfor maximum homology. “Looped” out sequences from deletions orinsertions, or mismatches, are considered differences.) The differencesare, preferably, differences or changes at a non-essential residue or aconservative substitution. In a preferred embodiment the differences arenot in the identified or conserved domain(s) within SEQ ID NO: 2, 5, 12,21, 26, 30, 36, 39, 42, 74, 77 or 87. In another embodiment one or moredifferences are in the cidentified or conserved domain(s) within SEQ IDNO: 2, 5, 12, 21, 26, 30, 36, 39, 42, 74, 77 or 87.

[0498] Other embodiments include a protein that contains one or morechanges in amino acid sequence, e.g., a change in an amino acid residuewhich is not essential for activity. Such 27877, 18080, 14081, 32140,50352, 16658, 14223, 16002, 50566, 65552 or 65577 proteins differ inamino acid sequence from SEQ ID NO: 2, 5, 12, 21, 26, 30, 36, 39, 42,74, 77 or 87, yet retain biological activity.

[0499] In one embodiment, the protein includes an amino acid sequence atleast about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98% or morehomologous to SEQ ID NO: 2, 5, 12, 21, 26, 30, 36, 39, 42, 74, 77 or 87.

[0500] A 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566,65552 or 65577 protein or fragment is provided which varies from thesequence of SEQ ID NO: 2, 5, 12, 21, 26, 30, 36, 39, 42, 74, 77 or 87 inregions defined by amino acids that are not within identified orconserved domains or regions by at least one but by less than 15, 10 or5 amino acid residues in the protein or fragment but which does notdiffer from SEQ ID NO: 2, 5, 12, 21, 26, 30, 36, 39, 42, 74, 77 or 87 inregions defined by amino acids that are within identified or conserveddomains or regions. (If this comparison requires alignment the sequencesshould be aligned for maximum homology. “Looped” out sequences fromdeletions or insertions, or mismatches, are considered differences.) Insome embodiments the difference is at a non-essential residue or is aconservative substitution, while in others the difference is at anessential residue or is a non-conservative substitution.

[0501] In one embodiment, a biologically active portion of a 27877,18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577protein includes an identified domain (refer to section for eachmolecule of the invention). Moreover, other biologically activeportions, in which other regions of the protein are deleted, can beprepared by recombinant techniques and evaluated for one or more of thefunctional activities of a native 27877, 18080, 14081, 32140, 50352,16658, 14223, 16002, 50566, 65552 or 65577 protein.

[0502] In a preferred embodiment, the 27877, 18080, 14081, 32140, 50352,16658, 14223, 16002, 50566, 65552 or 65577 protein has an amino acidsequence shown in SEQ ID NO: 2, 5, 12, 21, 26, 30, 36, 39, 42, 74, 77 or87. In other embodiments, the 27877, 18080, 14081, 32140, 50352, 16658,14223, 16002, 50566, 65552 or 65577 protein is sufficiently orsubstantially identical to SEQ ID NO: 2, 5, 12, 21, 26, 30, 36, 39, 42,74, 77 or 87. In yet another embodiment, the 27877, 18080, 14081, 32140,50352, 16658, 14223, 16002, 50566, 65552 or 65577 protein issufficiently or substantially identical to SEQ ID NO: 2, 5, 12, 21, 26,30, 36, 39, 42, 74, 77 or 87 and retains the functional activity of theprotein of SEQ ID NO: 2, 5, 12, 21, 26, 30, 36, 39, 42, 74, 77 or 87, asdescribed in detail in the subsections above.

[0503] 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566,65552 or 65577 Chimeric or Fusion Proteins

[0504] In another aspect, the invention provides 27877, 18080, 14081,32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 chimeric orfusion proteins. As used herein, a 27877, 18080, 14081, 32140, 50352,16658, 14223, 16002, 50566, 65552 or 65577 “chimeric protein” or “fusionprotein” includes a 27877, 18080, 14081, 32140, 50352, 16658, 14223,16002, 50566, 65552 or 65577 polypeptide linked to a non-27877, 18080,14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577polypeptide. A “non-27877, 18080, 14081, 32140, 50352, 16658, 14223,16002, 50566, 65552 or 65577 polypeptide” refers to a polypeptide havingan amino acid sequence corresponding to a protein which is notsubstantially homologous to the 27877, 18080, 14081, 32140, 50352,16658, 14223, 16002, 50566, 65552 or 65577 protein, e.g., a proteinwhich is different from the 27877, 18080, 14081, 32140, 50352, 16658,14223, 16002, 50566, 65552 or 65577 protein and which is derived fromthe same or a different organism. The 27877, 18080, 14081, 32140, 50352,16658, 14223, 16002, 50566, 65552 or 65577 polypeptide of the fusionprotein can correspond to all or a portion e.g., a fragment describedherein of a 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577 amino acid sequence. In a preferred embodiment, a27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or65577 fusion protein includes at least one (or two) biologically activeportion of a 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577 protein. The non-27877, 18080, 14081, 32140,50352, 16658, 14223, 16002, 50566, 65552 or 65577 polypeptide can befused to the N-terminus or C-terminus of the 27877, 18080, 14081, 32140,50352, 16658, 14223, 16002, 50566, 65552 or 65577 polypeptide.

[0505] The fusion protein can include a moiety which has a high affinityfor a ligand. For example, the fusion protein can be a GST-27877, 18080,14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 fusionprotein in which the 27877, 18080, 14081, 32140, 50352, 16658, 14223,16002, 50566, 65552 or 65577 sequences are fused to the C-terminus ofthe GST sequences. Such fusion proteins can facilitate the purificationof recombinant 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577. Alternatively, the fusion protein can be a 27877,18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577protein containing a heterologous signal sequence at its N-terminus. Incertain host cells (e.g., mammalian host cells), expression and/orsecretion of 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577 can be increased through use of a heterologoussignal sequence.

[0506] Fusion proteins can include all or a part of a serum protein,e.g., a portion of an immunoglobulin (e.g., IgG, IgA, or IgE), e.g., anFc region and/or the hinge C1 and C2 sequences of an immunoglobulin orhuman serum albumin.

[0507] The 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577 fusion proteins of the invention can beincorporated into pharmaceutical compositions and administered to asubject in vivo. The 27877, 18080, 14081, 32140, 50352, 16658, 14223,16002, 50566, 65552 or 65577 fusion proteins can be used to affect thebioavailability of a 27877, 18080, 14081, 32140, 50352, 16658, 14223,16002, 50566, 65552 or 65577 substrate. 27877, 18080, 14081, 32140,50352, 16658, 14223, 16002, 50566, 65552 or 65577 fusion proteins can beuseful therapeutically for the treatment of disorders caused by, forexample, (i) aberrant modification or mutation of a gene encoding a27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or65577 protein; (ii) mis-regulation of the 27877, 18080, 14081, 32140,50352, 16658, 14223, 16002, 50566, 65552 or 65577 gene; and (iii)aberrant post-translational modification of a 27877, 18080, 14081,32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 protein.

[0508] Moreover, the 27877, 18080, 14081, 32140, 50352, 16658, 14223,16002, 50566, 65552 or 65577-fusion proteins of the invention can beused as immunogens to produce anti-27877, 18080, 14081, 32140, 50352,16658, 14223, 16002, 50566, 65552 or 65577 antibodies in a subject, topurify 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566,65552 or 65577 ligands and in screening assays to identify moleculeswhich inhibit the interaction of 27877, 18080, 14081, 32140, 50352,16658, 14223, 16002, 50566, 65552 or 65577 with a 27877, 18080, 14081,32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 substrate.

[0509] Expression vectors are commercially available that already encodea fusion moiety (e.g., a GST polypeptide). A 27877, 18080, 14081, 32140,50352, 16658, 14223, 16002, 50566, 65552 or 65577-encoding nucleic acidcan be cloned into such an expression vector such that the fusion moietyis linked in-frame to the 27877, 18080, 14081, 32140, 50352, 16658,14223, 16002, 50566, 65552 or 65577 protein.

[0510] Variants of 27877, 18080, 14081, 32140, 50352, 16658, 14223,16002, 50566, 65552 or 65577 Proteins

[0511] In another aspect, the invention also features a variant of a27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or65577 polypeptide, e.g., which functions as an agonist (mimetics) or asan antagonist. Variants of the 27877, 18080, 14081, 32140, 50352, 16658,14223, 16002, 50566, 65552 or 65577 proteins can be generated bymutagenesis, e.g., discrete point mutation, the insertion or deletion ofsequences or the truncation of a 27877, 18080, 14081, 32140, 50352,16658, 14223, 16002, 50566, 65552 or 65577 protein. An agonist of the27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or65577 proteins can retain substantially the same, or a subset, of thebiological activities of the naturally occurring form of a 27877, 18080,14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 protein.An antagonist of a 27877, 18080, 14081, 32140, 50352, 16658, 14223,16002, 50566, 65552 or 65577 protein can inhibit one or more of theactivities of the naturally occurring form of the 27877, 18080, 14081,32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 protein by, forexample, competitively modulating a 27877, 18080, 14081, 32140, 50352,16658, 14223, 16002, 50566, 65552 or 65577-mediated activity of a 27877,18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577protein. Thus, specific biological effects can be elicited by treatmentwith a variant of limited function. Preferably, treatment of a subjectwith a variant having a subset of the biological activities of thenaturally occurring form of the protein has fewer side effects in asubject relative to treatment with the naturally occurring form of the27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or65577 protein.

[0512] Variants of a 27877, 18080, 14081, 32140, 50352, 16658, 14223,16002, 50566, 65552 or 65577 protein can be identified by screeningcombinatorial libraries of mutants, e.g., truncation mutants, of a27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or65577 protein for agonist or antagonist activity.

[0513] Libraries of fragments e.g., N terminal, C terminal, or internalfragments, of a 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577 protein coding sequence can be used to generate avariegated population of fragments for screening and subsequentselection of variants of a 27877, 18080, 14081, 32140, 50352, 16658,14223, 16002, 50566, 65552 or 65577 protein.

[0514] Variants in which a cysteine residues is added or deleted or inwhich a residue which is glycosylated is added or deleted areparticularly preferred.

[0515] Methods for screening gene products of combinatorial librariesmade by point mutations or truncation, and for screening cDNA librariesfor gene products having a selected property are known in the art.Recursive ensemble mutagenesis (REM), a new technique which enhances thefrequency of functional mutants in the libraries, can be used incombination with the screening assays to identify 27877, 18080, 14081,32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 variants (Arkinand Yourvan (1992) Proc. Natl. Acad. Sci. USA 89:7811-7815; Delgrave etal. (1993) Protein Engineering 6:327-331).

[0516] Cell based assays can be exploited to analyze a variegated 27877,18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577library. For example, a library of expression vectors can be transfectedinto a cell line, e.g., a cell line, which ordinarily responds to 27877,18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577in a substrate-dependent manner. The transfected cells are thencontacted with 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577 and the effect of the expression of the mutant onsignaling by the 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577 substrate can be detected, e.g., by measuringeither phospholipase activity, serine carboxypeptidase activity,trypsin-like serine protease activity, aldehyde dehydrogenase activity,ubiquitin-protein ligase activity, protein kinase activity, hydrolaseactivity, matrix metalloproteinase activity, or other activity. PlasmidDNA can then be recovered from the cells which score for inhibition, oralternatively, potentiation of signaling by the 27877, 18080, 14081,32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 substrate, andthe individual clones further characterized.

[0517] In another aspect, the invention features a method of making a27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or65577 polypeptide, e.g., a peptide having a non-wild type activity,e.g., an antagonist, agonist, or super agonist of a naturally occurring27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or65577 polypeptide, e.g., a naturally occurring 27877, 18080, 14081,32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 polypeptide.The method includes altering the sequence of a 27877, 18080, 14081,32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 polypeptide,e.g., altering the sequence, e.g., by substitution or deletion of one ormore residues of a non-conserved region, a domain or residue disclosedherein, and testing the altered polypeptide for the desired activity.

[0518] In another aspect, the invention features a method of making afragment or analog of a 27877, 18080, 14081, 32140, 50352, 16658, 14223,16002, 50566, 65552 or 65577 polypeptide a biological activity of anaturally occurring 27877, 18080, 14081, 32140, 50352, 16658, 14223,16002, 50566, 65552 or 65577 polypeptide. The method includes alteringthe sequence, e.g., by substitution or deletion of one or more residues,of a 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566,65552 or 65577 polypeptide, e.g., altering the sequence of anon-conserved region, or a domain or residue described herein, andtesting the altered polypeptide for the desired activity.

[0519] Anti-27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577 Antibodies

[0520] In another aspect, the invention provides an anti-27877, 18080,14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577antibody. The term “antibody” as used herein refers to an immunoglobulinmolecule or immunologically active portion thereof, i.e., anantigen-binding portion. Examples of immunologically active portions ofimmunoglobulin molecules include scFV and dcFV fragments, Fab andF(ab′)₂ fragments which can be generated by treating the antibody withan enzyme such as papain or pepsin, respectively.

[0521] The antibody can be a polyclonal, monoclonal, recombinant, e.g.,a chimeric or humanized, fully human, non-human, e.g., murine, or singlechain antibody. In a preferred embodiment it has effector function andcan fix complement. The antibody can be coupled to a toxin or imagingagent.

[0522] A full-length 27877, 18080, 14081, 32140, 50352, 16658, 14223,16002, 50566, 65552 or 65577 protein or, antigenic peptide fragment of27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or65577 can be used as an immunogen or can be used to identify anti-27877,18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577antibodies made with other immunogens, e.g., cells, membranepreparations, and the like. The antigenic peptide of 27877, 18080,14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 shouldinclude at least 8 amino acid residues of the amino acid sequence shownin SEQ ID NO: 2, 5, 12, 21, 26, 30, 36, 39, 42, 74, 77 or 87 andencompasses an epitope of 27877, 18080, 14081, 32140, 50352, 16658,14223, 16002, 50566, 65552 or 65577. Preferably, the antigenic peptideincludes at least 10 amino acid residues, more preferably at least 15amino acid residues, even more preferably at least 20 amino acidresidues, and most preferably at least 30 amino acid residues.

[0523] Fragments of 27877, 18080, 14081, 32140, 50352, 16658, 14223,16002, 50566, 65552 or 65577 which include hydrophilic regions of SEQ IDNO: 2, 5, 12, 21, 26, 30, 36, 39, 42, 74, 77 or 87 can be used to make,e.g., used as immunogens or used to characterize the specificity of anantibody, antibodies against hydrophilic regions of the 27877, 18080,14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 protein.Similarly, fragments of 27877, 18080, 14081, 32140, 50352, 16658, 14223,16002, 50566, 65552 or 65577 which include hydrophobic regions of SEQ IDNO: 2, 5, 12, 21, 26, 30, 36, 39, 42, 74, 77 or 87 can be used to makean antibody against a hydrophobic region of the 27877, 18080, 14081,32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 protein;fragments of 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577 which include residues within extra cellulardomain(s) of SEQ ID NO: 2, 5, 12, 21, 26, 30, 36, 39, 42, 74, 77 or 87can be used to make an antibody against an extracellular ornon-cytoplasmic region of the 27877, 18080, 14081, 32140, 50352, 16658,14223, 16002, 50566, 65552 or 65577 protein; fragments of 27877, 18080,14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 whichinclude residues within intracellular regions of SEQ ID NO: 2, 5, 12,21, 26, 30, 36, 39, 42, 74, 77 or 87 can be used to make an antibodyagainst an intracellular region of the 27877, 18080, 14081, 32140,50352, 16658, 14223, 16002, 50566, 65552 or 65577 protein; a fragment of27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or65577 which include residues within identified or conserved domains ofSEQ ID NO: 2, 5, 12, 21, 26, 30, 36, 39, 42, 74, 77 or 87 can be used tomake an antibody against the identified or conserved domain of the27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or65577 protein.

[0524] Antibodies reactive with, or specific or selective for, any ofthese regions, or other regions or domains described herein areprovided.

[0525] Preferred epitopes encompassed by the antigenic peptide areregions of 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577 located on the surface of the protein, e.g.,hydrophilic regions, as well as regions with high antigenicity. Forexample, an Emini surface probability analysis of the human 27877,18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577protein sequence can be used to indicate the regions that have aparticularly high probability of being localized to the surface of the27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or65577 protein and are thus likely to constitute surface residues usefulfor targeting antibody production.

[0526] In a preferred embodiment the antibody can bind to theextracellular portion of the 27877, 18080, 14081, 32140, 50352, 16658,14223, 16002, 50566, 65552 or 65577 protein, e.g., it can bind to awhole cell which expresses the 27877, 18080, 14081, 32140, 50352, 16658,14223, 16002, 50566, 65552 or 65577 protein. In another embodiment, theantibody binds an intracellular portion of the 27877, 18080, 14081,32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 protein.

[0527] In a preferred embodiment the antibody binds an epitope on anydomain or region on 27877, 18080, 14081, 32140, 50352, 16658, 14223,16002, 50566, 65552 or 65577 proteins described herein.

[0528] Additionally, chimeric, humanized, and completely humanantibodies are also within the scope of the invention. Chimeric,humanized, but most preferably, completely human antibodies aredesirable for applications which include repeated administration, e.g.,therapeutic treatment of human patients, and some diagnosticapplications.

[0529] Chimeric and humanized monoclonal antibodies, comprising bothhuman and non-human portions, can be made using standard recombinant DNAtechniques. Such chimeric and humanized monoclonal antibodies can beproduced by recombinant DNA techniques known in the art, for exampleusing methods described in Robinson et al. International Application No.PCT/US86/02269; Akira, et al. European Patent Application 184,187;Taniguchi, European Patent Application 171,496; Morrison et al. EuropeanPatent Application 173,494; Neuberger et al. PCT InternationalPublication No. WO 86/01533; Cabilly et al. U.S. Pat. No. 4,816,567;Cabilly et al. European Patent Application 125,023; Better et al. (1988)Science 240:1041-1043; Liu et al. (1987) Proc. Natl. Acad. Sci. USA84:3439-3443; Liu et al. (1987) J. Immunol. 139:3521-3526; Sun et al.(1987) Proc. Natl. Acad. Sci. USA 84:214-218; Nishimura et al. (1987)Canc. Res. 47:999-1005; Wood et al. (1985) Nature 314:446-449; and Shawet al. (1988) J. Natl. Cancer Inst. 80:1553-1559).

[0530] A humanized or complementarity determining region (CDR)-graftedantibody will have at least one or two, but generally all threerecipient CDR's (of heavy and or light immuoglobulin chains) replacedwith a donor CDR. The antibody may be replaced with at least a portionof a non-human CDR or only some of the CDR's may be replaced withnon-human CDR's. It is only necessary to replace the number of CDR'srequired for binding of the humanized antibody to a 27877, 18080, 14081,32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 or a fragmentthereof. Preferably, the donor will be a rodent antibody, e.g., a rat ormouse antibody, and the recipient will be a human framework or a humanconsensus framework. Typically, the immunoglobulin providing the CDR'sis called the “donor” and the immunoglobulin providing the framework iscalled the “acceptor.” In one embodiment, the donor immunoglobulin is anon-human (e.g., rodent). The acceptor framework is anaturally-occurring (e.g., a human) framework or a consensus framework,or a sequence about 85% or higher, preferably 90%, 95%, 99% or higheridentical thereto.

[0531] As used herein, the term “consensus sequence” refers to thesequence formed from the most frequently occurring amino acids (ornucleotides) in a family of related sequences (See e.g., Winnaker,(1987) From Genes to Clones (Verlagsgesellschaft, Weinheim; Germany). Ina family of proteins, each position in the consensus sequence isoccupied by the amino acid occurring most frequently at that position inthe family. If two amino acids occur equally frequently, either can beincluded in the consensus sequence. A “consensus framework” refers tothe framework region in the consensus immunoglobulin sequence.

[0532] An antibody can be humanized by methods known in the art.Humanized antibodies can be generated by replacing sequences of the Fvvariable region which are not directly involved in antigen binding withequivalent sequences from human Fv variable regions. General methods forgenerating humanized antibodies are provided by Morrison (1985) Science229:1202-1207, by Oi et al. (1986) BioTechniques 4:214, and by Queen etal. U.S. Pat. Nos. 5,585,089, 5,693,761 and 5,693,762, the contents ofall of which are hereby incorporated by reference. Those methods includeisolating, manipulating, and expressing the nucleic acid sequences thatencode all or part of immunoglobulin Fv variable regions from at leastone of a heavy or light chain. Sources of such nucleic acid are wellknown to those skilled in the art and, for example, may be obtained froma hybridoma producing an antibody against a 27877, 18080, 14081, 32140,50352, 16658, 14223, 16002, 50566, 65552 or 65577 polypeptide orfragment thereof. The recombinant DNA encoding the humanized antibody,or fragment thereof, can then be cloned into an appropriate expressionvector.

[0533] Humanized or CDR-grafted antibodies can be produced byCDR-grafting or CDR substitution, wherein one, two, or all CDR's of animmunoglobulin chain can be replaced. See e.g., U.S. Pat. No. 5,225,539;Jones et al. (1986) Nature 321:552-525; Verhoeyan et al. (1988) Science239:1534; Beidler et al. (1988) J. Immunol. 141:4053-4060; Winter U.S.Pat. No. 5,225,539, the contents of all of which are hereby expresslyincorporated by reference. Winter describes a CDR-grafting method whichmay be used to prepare the humanized antibodies of the present invention(UK Patent Application GB 2188638A, filed on Mar. 26, 1987; Winter U.S.Pat. No. 5,225,539), the contents of which is expressly incorporated byreference.

[0534] Also within the scope of the invention are humanized antibodiesin which specific amino acids have been substituted, deleted or added.Preferred humanized antibodies have amino acid substitutions in theframework region, such as to improve binding to the antigen. Forexample, a humanized antibody will have framework residues identical tothe donor framework residue or to another amino acid other than therecipient framework residue. To generate such antibodies, a selected,small number of acceptor framework residues of the humanizedimmunoglobulin chain can be replaced by the corresponding donor aminoacids. Preferred locations of the substitutions include amino acidresidues adjacent to the CDR, or which are capable of interacting with aCDR (see e.g., U.S. Pat. No. 5,585,089). Criteria for selecting aminoacids from the donor are described in U.S. Pat. No. 5,585,089, e.g.,columns 12-16 of U.S. Pat. No. 5,585,089, the e.g., columns 12-16 ofU.S. Pat. No. 5,585,089, the contents of which are hereby incorporatedby reference. Other techniques for humanizing antibodies are describedin Padlan et al. EP 519596 A1, published on Dec. 23, 1992.

[0535] Completely human antibodies are particularly desirable fortherapeutic treatment of human patients. Such antibodies can be producedusing transgenic mice that are incapable of expressing endogenousimmunoglobulin heavy and light chains genes, but which can express humanheavy and light chain genes. See, for example, Lonberg and Huszar (1995)Int. Rev. Immunol. 13:65-93); and U.S. Pat. Nos. 5,625,126; 5,633,425;5,569,825; 5,661,016; and 5,545,806. In addition, companies such asAbgenix, Inc. (Fremont, Calif.) and Medarex, Inc. (Princeton, N.J.), canbe engaged to provide human antibodies directed against a selectedantigen using technology similar to that described above.

[0536] Completely human antibodies that recognize a selected epitope canbe generated using a technique referred to as “guided selection.” Inthis approach a selected non-human monoclonal antibody, e.g., a murineantibody, is used to guide the selection of a completely human antibodyrecognizing the same epitope. This technology is described by Jespers etal. (1994) Bio/Technology 12:899-903).

[0537] The anti-27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577 antibody can be a single chain antibody. Asingle-chain antibody (scFV) can be engineered as described in, forexample, Colcher et al. (1999) Ann. N.Y. Acad. Sci. 880:263-80; andReiter (1996) Clin. Cancer Res. 2:245-52. The single chain antibody canbe dimerized or multimerized to generate multivalent antibodies havingspecificities for different epitopes of the same target 27877, 18080,14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 protein.

[0538] In a preferred embodiment, the antibody has reduced or no abilityto bind an Fc receptor. For example, it is an isotype or subtype,fragment or other mutant, which does not support binding to an Fcreceptor, e.g., it has a mutagenized or deleted Fc receptor bindingregion.

[0539] An antibody (or fragment thereof) may be conjugated to atherapeutic moiety such as a cytotoxin, a therapeutic agent or aradioactive ion. A cytotoxin or cytotoxic agent includes any agent thatis detrimental to cells. Examples include taxol, cytochalasin B,gramicidin D, ethidium bromide, emetine, mitomycin, etoposide,tenoposide, vincristine, vinblastine, colchicin, doxorubicin,daunorubicin, dihydroxy anthracin dione, mitoxantrone, mithramycin,actinomycin D, 1-dehydrotestosterone, glucocorticoids, procaine,tetracaine, lidocaine, propranolol, puromycin, maytansinoids, e.g.,maytansinol (see U.S. Pat. No. 5,208,020), CC-1065 (see U.S. Pat. Nos.5,475,092, 5,585,499, 5,846,545) and analogs or homologs thereof.Therapeutic agents include, but are not limited to, antimetabolites(e.g., methotrexate, 6-mercaptopurine, 6-thioguanine, cytarabine,5-fluorouracil decarbazine), alkylating agents (e.g., mechlorethamine,thioepa chlorambucil, CC-1065, melphalan, carmustine (BSNU) andlomustine (CCNU), cyclothosphamide, busulfan, dibromomannitol,streptozotocin, mitomycin C, and cis-dichlorodiamine platinum (II) (DDP)cisplatin), anthracyclines (e.g., daunorubicin (formerly daunomycin) anddoxorubicin), antibiotics (e.g., dactinomycin (formerly actinomycin),bleomycin, mithramycin, and anthramycin (AMC)), and anti-mitotic agents(e.g., vincristine, vinblastine, taxol and maytansinoids).

[0540] Radioactive ions include, but are not limited to iodine, yttriumand praseodymium.

[0541] The conjugates of the invention can be used for modifying a givenbiological response, the therapeutic moiety is not to be construed aslimited to classical chemical therapeutic agents. For example, thetherapeutic moiety may be a protein or polypeptide possessing a desiredbiological activity. Such proteins may include, for example, a toxinsuch as abrin, ricin A, pseudomonas exotoxin, or diphtheria toxin; aprotein such as tumor necrosis factor, α-interferon, β-interferon, nervegrowth factor, platelet derived growth factor, tissue plasminogenactivator; or, biological response modifiers such as, for example,lymphokines, interleukin-1 (“IL-1”), interleukin-2 (“IL-2”),interleukin-6 (“IL-6”), granulocyte macrophase colony stimulating factor(“GM-CSF”), granulocyte colony stimulating factor (“G-CSF”), or othergrowth factors.

[0542] Alternatively, an antibody can be conjugated to a second antibodyto form an antibody heteroconjugate as described by Segal in U.S. Pat.No. 4,676,980.

[0543] An anti-27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577 antibody (e.g., monoclonal antibody) can be usedto isolate 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577 by standard techniques, such as affinitychromatography or immunoprecipitation. Moreover, an anti-27877, 18080,14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 antibodycan be used to detect 27877, 18080, 14081, 32140, 50352, 16658, 14223,16002, 50566, 65552 or 65577 protein (e.g., in a cellular lysate or cellsupernatant) in order to evaluate the abundance and pattern ofexpression of the protein. Anti-27877, 18080, 14081, 32140, 50352,16658, 14223, 16002, 50566, 65552 or 65577 antibodies can be useddiagnostically to monitor protein levels in tissue as part of a clinicaltesting procedure, e.g., to determine the efficacy of a given treatmentregimen. Detection can be facilitated by coupling (i.e., physicallylinking) the antibody to a detectable substance (i.e., antibodylabelling). Examples of detectable substances include various enzymes,prosthetic groups, fluorescent materials, luminescent materials,bioluminescent materials, and radioactive materials. Examples ofsuitable enzymes include horseradish peroxidase, alkaline phosphatase,β-galactosidase, or acetylcholinesterase; examples of suitableprosthetic group complexes include streptavidin/biotin andavidin/biotin; examples of suitable fluorescent materials includeumbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine,dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin; anexample of a luminescent material includes luminol; examples ofbioluminescent materials include luciferase, luciferin, and aequorin,and examples of suitable radioactive material include ¹²⁵I, ¹³¹I, ³⁵S or³H.

[0544] In preferred embodiments, an antibody can be made by immunizingwith a purified 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577 antigen, or a fragment thereof, e.g., a fragmentdescribed herein, a membrane associated antigen, tissues, e.g., crudetissue preparations, whole cells, preferably living cells, lysed cells,or cell fractions, e.g., membrane fractions.

[0545] Antibodies which bind only a native 27877, 18080, 14081, 32140,50352, 16658, 14223, 16002, 50566, 65552 or 65577 protein, onlydenatured or otherwise non-native 27877, 18080, 14081, 32140, 50352,16658, 14223, 16002, 50566, 65552 or 65577 protein, or which bind both,are within the invention. Antibodies with linear or conformationalepitopes are within the invention. Conformational epitopes sometimes canbe identified by identifying antibodies which bind to native but notdenatured 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566,65552 or 65577 protein. Recombinant Expression Vectors, Host Cells andGenetically Engineered Cells

[0546] In another aspect, the invention includes, vectors, preferablyexpression vectors, containing a nucleic acid encoding a polypeptidedescribed herein. As used herein, the term “vector” refers to a nucleicacid molecule capable of transporting another nucleic acid to which ithas been linked and can include a plasmid, cosmid or viral vector. Thevector can be capable of autonomous replication or it can integrate intoa host DNA. Viral vectors include, e.g., replication defectiveretroviruses, adenoviruses and adeno-associated viruses.

[0547] A vector can include a 27877, 18080, 14081, 32140, 50352, 16658,14223,-16002, 50566, 65552 or 65577 nucleic acid in a form suitable forexpression of the nucleic acid in a host cell.

[0548] Preferably the recombinant expression vector includes one or moreregulatory sequences operatively linked to the nucleic acid sequence tobe expressed. The term “regulatory sequence” includes promoters,enhancers and other expression control elements (e.g., polyadenylationsignals). Regulatory sequences include those which direct constitutiveexpression of a nucleotide sequence, as well as tissue-specificregulatory and/or inducible sequences. The design of the expressionvector can depend on such factors as the choice of the host cell to betransformed, the level of expression of protein desired, and the like.The expression vectors of the invention can be introduced into hostcells to thereby produce proteins or polypeptides, including fusionproteins or polypeptides, encoded by nucleic acids as described herein(e.g., 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566,65552 or 65577 proteins, mutant forms of 27877, 18080, 14081, 32140,50352, 16658, 14223, 16002, 50566, 65552 or 65577 proteins, fusionproteins, and the like).

[0549] The recombinant expression vectors of the invention can bedesigned for expression of 27877, 18080, 14081, 32140, 50352, 16658,14223, 16002, 50566, 65552 or 65577 proteins in prokaryotic oreukaryotic cells. For example, polypeptides of the invention can beexpressed in E. coli, insect cells (e.g., using baculovirus expressionvectors), yeast cells or mammalian cells. Suitable host cells arediscussed further in Goeddel, (1990) Gene Expression Technology: Methodsin Enzymology 185, Academic Press, San Diego, Calif. Alternatively, therecombinant expression vector can be transcribed and translated invitro, for example using T7 promoter regulatory sequences and T7polymerase.

[0550] Expression of proteins in prokaryotes is most often carried outin E. coli with vectors containing constitutive or inducible promotersdirecting the expression of either fusion or non-fusion proteins. Fusionvectors add a number of amino acids to a protein encoded therein,usually to the amino terminus of the recombinant protein. Such fusionvectors typically serve three purposes: 1) to increase expression ofrecombinant protein; 2) to increase the solubility of the recombinantprotein; and 3) to aid in the purification of the recombinant protein byacting as a ligand in affinity purification. Often, a proteolyticcleavage site is introduced at the junction of the fusion moiety and therecombinant protein to enable separation of the recombinant protein fromthe fusion moiety subsequent to purification of the fusion protein. Suchenzymes, and their cognate recognition sequences, include Factor Xa,thrombin and enterokinase. Typical fusion expression vectors includepGEX (Pharmacia Biotech Inc; Smith and Johnson (1988) Gene 67:31-40),pMAL (New England Biolabs, Beverly, Mass.) and pRIT5 (Pharmacia,Piscataway, N.J.) which fuse glutathione S-transferase (GST), maltose Ebinding protein, or protein A, respectively, to the target recombinantprotein.

[0551] Purified fusion proteins can be used in 27877, 18080, 14081,32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 activityassays, (e.g., direct assays or competitive assays described in detailbelow), or to generate antibodies specific or selective for 27877,18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577proteins. In a preferred embodiment, a fusion protein expressed in aretroviral expression vector of the present invention can be used toinfect bone marrow cells which are subsequently transplanted intoirradiated recipients. The pathology of the subject recipient is thenexamined after sufficient time has passed (e.g., six weeks).

[0552] To maximize recombinant protein expression in E. coli is toexpress the protein in a host bacteria with an impaired capacity toproteolytically cleave the recombinant protein (Gottesman (1990) GeneExpression Technology: Methods in Enzymology 185, Academic Press, SanDiego, Calif. 119-128). Another strategy is to alter the nucleic acidsequence of the nucleic acid to be inserted into an expression vector sothat the individual codons for each amino acid are those preferentiallyutilized in E. coli (Wada et al., (1992) Nucleic Acids Res.20:2111-2118). Such alteration of nucleic acid sequences of theinvention can be carried out by standard DNA synthesis techniques.

[0553] The 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577 expression vector can be a yeast expressionvector, a vector for expression in insect cells, e.g., a baculovirusexpression vector or a vector suitable for expression in mammaliancells.

[0554] When used in mammalian cells, the expression vector's controlfunctions are often provided by viral regulatory elements. For example,commonly used promoters are derived from polyoma, Adenovirus 2,cytomegalovirus and Simian Virus 40.

[0555] In another embodiment, the recombinant mammalian expressionvector is capable of directing expression of the nucleic acidpreferentially in a particular cell type (e.g., tissue-specificregulatory elements are used to express the nucleic acid). Non-limitingexamples of suitable tissue-specific promoters include the albuminpromoter (liver-specific; Pinkert et al. (1987) Genes Dev. 1:268-277),lymphoid-specific promoters (Calame and Eaton (1988) Adv. Immunol.43:235-275), in particular promoters of T cell receptors (Winoto andBaltimore (1989) EMBO J. 8:729-733) and immunoglobulins (Banerji et al.(1983) Cell 33:729-740; Queen and Baltimore (1983) Cell 33:741-748),neuron-specific promoters (e.g., the neurofilament promoter; Byrne andRuddle (1989) Proc. Natl. Acad. Sci. USA 86:5473-5477),pancreas-specific promoters (Edlund et al. (1985) Science 230:912-916),and mammary gland-specific promoters (e.g., milk whey promoter; U.S.Pat. No. 4,873,316 and European Application Publication No. 264,166).Developmentally-regulated promoters are also encompassed, for example,the murine hox promoters (Kessel and Gruss (1990) Science 249:374-379)and the α-fetoprotein promoter (Campes and Tilghman (1989) Genes Dev.3:537-546).

[0556] The invention further provides a recombinant expression vectorcomprising a DNA molecule of the invention cloned into the expressionvector in an antisense orientation. Regulatory sequences (e.g., viralpromoters and/or enhancers) operatively linked to a nucleic acid clonedin the antisense orientation can be chosen which direct theconstitutive, tissue specific or cell type specific expression ofantisense RNA in a variety of cell types. The antisense expressionvector can be in the form of a recombinant plasmid, phagemid orattenuated virus. For a discussion of the regulation of gene expressionusing antisense genes see Weintraub et al., (1986) Reviews—Trends inGenetics 1:1.

[0557] Another aspect the invention provides a host cell which includesa nucleic acid molecule described herein, e.g., a 27877, 18080, 14081,32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 nucleic acidmolecule within a recombinant expression vector or a 27877, 18080,14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 nucleicacid molecule containing sequences which allow it to homologouslyrecombine into a specific site of the host cell's genome. The terms“host cell” and “recombinant host cell” are used interchangeably herein.Such terms refer not only to the particular subject cell but to theprogeny or potential progeny of such a cell. Because certainmodifications can occur in succeeding generations due to either mutationor environmental influences, such progeny may not, in fact, be identicalto the parent cell, but are still included within the scope of the termas used herein.

[0558] A host cell can be any prokaryotic or eukaryotic cell. Forexample, a 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577 protein can be expressed in bacterial cells suchas E. coli, insect cells, yeast or mammalian cells (such as Chinesehamster ovary (CHO) cells or CV-1 origin, SV-40 (COS) cells). Othersuitable host cells are known to those skilled in the art.

[0559] Vector DNA can be introduced into host cells via conventionaltransformation or transfection techniques. As used herein, the terms“transformation” and “transfection” are intended to refer to a varietyof art-recognized techniques for introducing foreign nucleic acid (e.g.,DNA) into a host cell, including calcium phosphate or calcium chlorideco-precipitation, DEAE-dextran-mediated transfection, lipofection, orelectroporation.

[0560] A host cell of the invention can be used to produce (i.e.,express) a 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577 protein. Accordingly, the invention furtherprovides methods for producing a 27877, 18080, 14081, 32140, 50352,16658, 14223, 16002, 50566, 65552 or 65577 protein using the host cellsof the invention. In one embodiment, the method includes culturing thehost cell of the invention (into which a recombinant expression vectorencoding a 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577 protein has been introduced) in a suitable mediumsuch that a 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577 protein is produced. In another embodiment, themethod further includes isolating a 27877, 18080, 14081, 32140, 50352,16658, 14223, 16002, 50566, 65552 or 65577 protein from the medium orthe host cell.

[0561] In another aspect, the invention features, a cell or purifiedpreparation of cells which include a 27877, 18080, 14081, 32140, 50352,16658, 14223, 16002, 50566, 65552 or 65577 transgene, or which otherwisemisexpress 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577. The cell preparation can consist of human ornon-human cells, e.g., rodent cells, e.g., mouse or rat cells, rabbitcells, or pig cells. In preferred embodiments, the cell or cells includea 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552or 65577 transgene, e.g , a heterologous form of a 27877, 18080, 14081,32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577, e.g., a genederived from humans (in the case of a non-human cell). The 27877, 18080,14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577transgene can be misexpressed, e.g., overexpressed or underexpressed. Inother preferred embodiments, the cell or cells include a gene whichmisexpresses an endogenous 27877, 18080, 14081, 32140, 50352, 16658,14223, 16002, 50566, 65552 or 65577, e.g., a gene the expression ofwhich is disrupted, e.g., a knockout. Such cells can serve as a modelfor studying disorders which are related to mutated or misexpressed27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or65577 alleles or for use in drug screening.

[0562] In another aspect, the invention features, a human cell, e.g., ahematopoietic stem cell, transformed with nucleic acid which encodes asubject 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566,65552 or 65577 polypeptide.

[0563] Also provided are cells, preferably human cells, e.g., humanhematopoietic or fibroblast cells, in which an endogenous 27877, 18080,14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 is underthe control of a regulatory sequence that does not normally control theexpression of the endogenous 27877, 18080, 14081, 32140, 50352, 16658,14223, 16002, 50566, 65552 or 65577 gene. The expression characteristicsof an endogenous gene within a cell, e.g., a cell line or microorganism,can be modified by inserting a heterologous DNA regulatory element intothe genome of the cell such that the inserted regulatory element isoperably linked to the endogenous 27877, 18080, 14081, 32140, 50352,16658, 14223, 16002, 50566, 65552 or 65577 gene. For example, anendogenous 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577 gene which is “transcriptionally silent,” e.g.,not normally expressed, or expressed only at very low levels, can beactivated by inserting a regulatory element which is capable ofpromoting the expression of a normally expressed gene product in thatcell. Techniques such as targeted homologous recombinations, can be usedto insert the heterologous DNA as described in, e.g., Chappel, U.S. Pat.No. 5,272,071; WO 91/06667, published in May 16, 1991.

[0564] Transgenic Animals

[0565] The invention provides non-human transgenic animals. Such animalsare useful for studying the function and/or activity of a 27877, 18080,14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 proteinand for identifying and/or evaluating modulators of 27877, 18080, 14081,32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 activity. Asused herein, a “transgenic animal” is a non-human animal, preferably amammal, more preferably a rodent such as a rat or mouse, in which one ormore of the cells of the animal includes a transgene. Other examples oftransgenic animals include non-human primates, sheep, dogs, cows, goats,chickens, amphibians, and the like. A transgene is exogenous DNA or arearrangement, e.g., a deletion of endogenous chromosomal DNA, whichpreferably is integrated into or occurs in the genome of the cells of atransgenic animal. A transgene can direct the expression of an encodedgene product in one or more cell types or tissues of the transgenicanimal, other transgenes, e.g., a knockout, reduce expression. Thus, atransgenic animal can be one in which an endogenous 27877, 18080, 14081,32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 gene has beenaltered by, e.g., by homologous recombination between the endogenousgene and an exogenous DNA molecule introduced into a cell of the animal,e.g., an embryonic cell of the animal, prior to development of theanimal.

[0566] Intronic sequences and polyadenylation signals can also beincluded in the transgene to increase the efficiency of expression ofthe transgene. A tissue-specific regulatory sequence(s) can be operablylinked to a transgene of the invention to direct expression of a 27877,18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577protein to particular cells. A transgenic founder animal can beidentified based upon the presence of a 27877, 18080, 14081, 32140,50352, 16658, 14223, 16002, 50566, 65552 or 65577 transgene in itsgenome and/or expression of 27877, 18080, 14081, 32140, 50352, 16658,14223, 16002, 50566, 65552 or 65577 mRNA in tissues or cells of theanimals. A transgenic founder animal can then be used to breedadditional animals carrying the transgene. Moreover, transgenic animalscarrying a transgene encoding a 27877, 18080, 14081, 32140, 50352,16658, 14223, 16002, 50566, 65552 or 65577 protein can further be bredto other transgenic animals carrying other transgenes.

[0567] 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566,65552 or 65577 proteins or polypeptides can be expressed in transgenicanimals or plants, e.g., a nucleic acid encoding the protein orpolypeptide can be introduced into the genome of an animal. In preferredembodiments the nucleic acid is placed under the control of a tissuespecific promoter, e.g., a milk or egg specific promoter, and recoveredfrom the milk or eggs produced by the animal. Suitable animals are mice,pigs, cows, goats, and sheep.

[0568] The invention also includes a population of cells from atransgenic animal, as discussed, e.g., below.

[0569] Uses

[0570] The nucleic acid molecules, proteins, protein homologs, andantibodies described herein can be used in one or more of the followingmethods: a) screening assays; b) predictive medicine (e.g. diagnosticassays, prognostic assays, monitoring clinical trials, andpharmacogenetics); and c) methods of treatment (e.g., therapeutic andprophylactic).

[0571] The isolated nucleic acid molecules of the invention can be used,for example, to express a 27877, 18080, 14081, 32140, 50352, 16658,14223, 16002, 50566, 65552 or 65577 protein (e.g., via a recombinantexpression vector in a host cell in gene therapy applications), todetect a 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566,65552 or 65577 mRNA (e.g., in a biological sample) or a geneticalteration in a 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577 gene, and to modulate 27877, 18080, 14081, 32140,50352, 16658, 14223, 16002, 50566, 65552 or 65577 activity, as describedfurther below. The 27877, 18080, 14081, 32140, 50352, 16658, 14223,16002, 50566, 65552 or 65577 proteins can be used to treat disorderscharacterized by insufficient or excessive production of a 27877, 18080,14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577substrate or production of 27877, 18080, 14081, 32140, 50352, 16658,14223, 16002, 50566, 65552 or 65577 inhibitors. In addition, the 27877,18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577proteins can be used to screen for naturally occurring 27877, 18080,14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577substrates, to screen for drugs or compounds which modulate 27877,18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577activity, as well as to treat disorders characterized by insufficient orexcessive production of 27877, 18080, 14081, 32140, 50352, 16658, 14223,16002, 50566, 65552 or 65577 protein or production of 27877, 18080,14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 proteinforms which have decreased, aberrant or unwanted activity compared to27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or65577 wild type protein (e.g., aberrant or deficient phospholipaseactivity, serine carboxypeptidase activity, trypsin-like serine proteaseactivity, aldehyde dehydrogenase activity, ubiquitin-protein ligaseactivity, protein kinase activity, hydrolase activity, matrixmetalloproteinase activity, or other activity). Moreover, theanti-27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566,65552 or 65577 antibodies of the invention can be used to detect andisolate 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566,65552 or 65577 proteins, regulate the bioavailability of 27877, 18080,14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577proteins, and modulate 27877, 18080, 14081, 32140, 50352, 16658, 14223,16002, 50566, 65552 or 65577 activity.

[0572] A method of evaluating a compound for the ability to interactwith, e.g., bind, a subject 27877, 18080, 14081, 32140, 50352, 16658,14223, 16002, 50566, 65552 or 65577 polypeptide is provided. The methodincludes: contacting the compound with the subject 27877, 18080, 14081,32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 polypeptide;and evaluating ability of the compound to interact with, e.g., to bindor form a complex with the subject 27877, 18080, 14081, 32140, 50352,16658, 14223, 16002, 50566, 65552 or 65577 polypeptide. This method canbe performed in vitro, e.g., in a cell free system, or in vivo, e.g., ina two-hybrid interaction trap assay. This method can be used to identifynaturally occurring molecules which interact with subject 27877, 18080,14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577polypeptide. It can also be used to find natural or synthetic inhibitorsof subject 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577 polypeptide. Screening methods are discussed inmore detail below.

[0573] Screening Assays:

[0574] The invention provides methods (also referred to herein as“screening assays”) for identifying modulators, i.e., candidate or testcompounds or agents (e.g., proteins, peptides, peptidomimetics,peptoids, small molecules or other drugs) which bind to 27877, 18080,14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577proteins, have a stimulatory or inhibitory effect on, for example,27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or65577 expression or 27877, 18080, 14081, 32140, 50352, 16658, 14223,16002, 50566, 65552 or 65577 activity, or have a stimulatory orinhibitory effect on, for example, the expression or activity of a27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or65577 substrate. Compounds thus identified can be used to modulate theactivity of target gene products (e.g., 27877, 18080, 14081, 32140,50352, 16658, 14223, 16002, 50566, 65552 or 65577 genes) in atherapeutic protocol, to elaborate the biological function of the targetgene product, or to identify compounds that disrupt normal target geneinteractions.

[0575] In one embodiment, the invention provides assays for screeningcandidate or test compounds which are substrates of a 27877, 18080,14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 proteinor polypeptide or a biologically active portion thereof. In anotherembodiment, the invention provides assays for screening candidate ortest compounds which bind to or modulate the activity of a 27877, 18080,14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 proteinor polypeptide or a biologically active portion thereof.

[0576] The test compounds of the present invention can be obtained usingany of the numerous approaches in combinatorial library methods known inthe art, including: biological libraries; peptoid libraries (librariesof molecules having the functionalities of peptides, but with a novel,non-peptide backbone which are resistant to enzymatic degradation butwhich nevertheless remain bioactive; see, e.g., Zuckermann et al. (1994)J. Med. Chem. 37:2678-85); spatially addressable parallel solid phase orsolution phase libraries; synthetic library methods requiringdeconvolution; the ‘one-bead one-compound’ library method; and syntheticlibrary methods using affinity chromatography selection. The biologicallibrary and peptoid library approaches are limited to peptide libraries,while the other four approaches are applicable to peptide, non-peptideoligomer or small molecule libraries of compounds (Lam (1997) AnticancerDrug Des. 12:145).

[0577] Examples of methods for the synthesis of molecular libraries canbe found in the art, for example in: DeWitt et al. (1993) Proc. Natl.Acad. Sci. U.S.A. 90:6909-13; Erb et al. (1994) Proc. Natl. Acad. Sci.USA 91:11422-426; Zuckermann et al. (1994). J. Med. Chem. 37:2678-85;Cho et al. (1993) Science 261:1303; Carrell et al. (1994) Angew. Chem.Int. Ed. Engl. 33:2059; Carell et al. (1994) Angew. Chem. Int. Ed. Engl.33:2061; and in Gallop et al. (1994) J. Med. Chem. 37:1233-51.

[0578] Libraries of compounds can be presented in solution (e.g.,Houghten (1992) Biotechniques 13:412-421), or on beads (Lam (1991)Nature 354:82-84), chips (Fodor (1993) Nature 364:555-556), bacteria(Ladner, U.S. Pat. No. 5,223,409), spores (Ladner U.S. Pat. No. '409),plasmids (Cull et al. (1992) Proc Natl Acad Sci USA 89:1865-1869) or onphage (Scott and Smith (1990) Science 249:386-390; Devlin (1990) Science249:404-406; Cwirla et al. (1990) Proc. Natl. Acad. Sci. 87:6378-6382;Felici (1991) J. Mol. Biol. 222:301-310; Ladner supra.).

[0579] In one embodiment, an assay is a cell-based assay in which a cellwhich expresses a 27877, 18080, 14081, 32140, 50352, 16658, 14223,16002, 50566, 65552 or 65577 protein or biologically active portionthereof is contacted with a test compound, and the ability of the testcompound to modulate 27877, 18080, 14081, 32140, 50352, 16658, 14223,16002, 50566, 65552 or 65577 activity is determined. Determining theability of the test compound to modulate 27877, 18080, 14081, 32140,50352, 16658, 14223, 16002, 50566, 65552 or 65577 activity can beaccomplished by monitoring, for example, phospholipase activity, serinecarboxypeptidase activity, trypsin-like serine protease activity,aldehyde dehydrogenase activity, ubiquitin-protein ligase activity,protein kinase activity, hydrolase activity, matrix metalloproteinaseactivity, or other activity. The cell, for example, can be of mammalianorigin, e.g., human.

[0580] The ability of the test compound to modulate 27877, 18080, 14081,32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 binding to acompound, e.g., a 27877, 18080, 14081, 32140, 50352, 16658, 14223,16002, 50566, 65552 or 65577 substrate, or to bind to 27877, 18080,14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 can alsobe evaluated. This can be accomplished, for example, by coupling thecompound, e.g., the substrate, with a radioisotope or enzymatic labelsuch that binding of the compound, e.g., the substrate, to 27877, 18080,14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 can bedetermined by detecting the labeled compound, e.g., substrate, in acomplex. Alternatively, 27877, 18080, 14081, 32140, 50352, 16658, 14223,16002, 50566, 65552 or 65577 could be coupled with a radioisotope orenzymatic label to monitor the ability of a test compound to modulate27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or65577 binding to a 27877, 18080, 14081, 32140, 50352, 16658, 14223,16002, 50566, 65552 or 65577 substrate in a complex. For example,compounds (e.g., 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or65577 substrates) can be labeled with ¹²⁵I, ¹⁴C, ³⁵S or³H., either directly or indirectly, and the radioisotope detected bydirect counting of radioemmission or by scintillation counting.Alternatively, compounds can be enzymatically labeled with, for example,horseradish peroxidase, alkaline phosphatase, or luciferase, and theenzymatic label detected by determination of conversion of anappropriate substrate to product.

[0581] The ability of a compound (e.g., a 27877, 18080, 14081, 32140,50352, 16658, 14223, 16002, 50566, 65552 or 65577 substrate) to interactwith 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566,65552 or 65577 with or without the labeling of any of the interactantscan be evaluated. For example, a microphysiometer can be used to detectthe interaction of a compound with 27877, 18080, 14081, 32140, 50352,16658, 14223, 16002, 50566, 65552 or 65577 without the labeling ofeither the compound or the 27877, 18080, 14081, 32140, 50352, 16658,14223, 16002, 50566, 65552 or 65577. McConnell et al. (1992) Science257:1906-1912. As used herein, a “microphysiometer” (e.g., Cytosensor)is an analytical instrument that measures the rate at which a cellacidifies its environment using a light-addressable potentiometricsensor (LAPS). Changes in this acidification rate can be used as anindicator of the interaction between a compound and 27877, 18080, 14081,32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577.

[0582] In yet another embodiment, a cell-free assay is provided in whicha 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552or 65577 protein or biologically active portion thereof is contactedwith a test compound and the ability of the test compound to bind to the27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or65577 protein or biologically active portion thereof is evaluated.Preferred biologically active portions of the 27877, 18080, 14081,32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 proteins to beused in assays of the present invention include fragments whichparticipate in interactions with non-27877, 18080, 14081, 32140, 50352,16658, 14223, 16002, 50566, 65552 or 65577 molecules, e.g., fragmentswith high surface probability scores.

[0583] Soluble and/or membrane-bound forms of isolated proteins (e.g.,27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or65577 proteins or biologically active portions thereof) can be used inthe cell-free assays of the invention. When membrane-bound forms of theprotein are used, it may be desirable to utilize a solubilizing agent.Examples of such solubilizing agents include non-ionic detergents suchas n-octylglucoside, n-dodecylglucoside, n-dodecylmaltoside,octanoyl-N-methylglucamide, decanoyl-N-methylglucamide, Triton® X-100,Triton® X-114, Thesit®, Isotridecypoly(ethylene glycol ether)_(n),3-[(3-cholamidopropyl)dimethylamminio]-1-propane sulfonate (CHAPS),3-[(3-cholamidopropyl)dimethylamminio]-2-hydroxy-1-propane sulfonate(CHAPSO), or N-dodecyl=N,N-dimethyl-3-ammonio-1-propane sulfonate.

[0584] Cell-free assays involve preparing a reaction mixture of thetarget gene protein and the test compound under conditions and for atime sufficient to allow the two components to interact and bind, thusforming a complex that can be removed and/or detected.

[0585] The interaction between two molecules can also be detected, e.g.,using fluorescence energy transfer (FET) (see, for example, Lakowicz etal., U.S. Pat. No. 5,631,169; Stavrianopoulos, et al., U.S. Pat. No.4,868,103). A fluorophore label on the first, ‘donor’ molecule isselected such that its emitted fluorescent energy will be absorbed by afluorescent label on a second, ‘acceptor’ molecule, which in turn isable to fluoresce due to the absorbed energy. Alternately, the ‘donor’protein molecule can simply utilize the natural fluorescent energy oftryptophan residues. Labels are chosen that emit different wavelengthsof light, such that the ‘acceptor’ molecule label can be differentiatedfrom that of the ‘donor’. Since the efficiency of energy transferbetween the labels is related to the distance separating the molecules,the spatial relationship between the molecules can be assessed. In asituation in which binding occurs between the molecules, the fluorescentemission of the ‘acceptor’ molecule label in the assay should bemaximal. An FET binding event can be conveniently measured throughstandard fluorometric detection means well known in the art (e.g., usinga fluorimeter).

[0586] In another embodiment, determining the ability of the 27877,18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577protein to bind to a target molecule can be accomplished using real-timeBiomolecular Interaction Analysis (BIA) (see, e.g., Sjolander andUrbaniczky (1991) Anal. Chem. 63:2338-2345 and Szabo et al. (1995) Curr.Opin. Struct. Biol. 5:699-705). “Surface plasmon resonance” or “BIA”detects biospecific interactions in real time, without labeling any ofthe interactants (e.g., BIAcore). Changes in the mass at the bindingsurface (indicative of a binding event) result in alterations of therefractive index of light near the surface (the optical phenomenon ofsurface plasmon resonance (SPR)), resulting in a detectable signal whichcan be used as an indication of real-time reactions between biologicalmolecules.

[0587] In one embodiment, the target gene product or the test substanceis anchored onto a solid phase. The target gene product/test compoundcomplexes anchored on the solid phase can be detected at the end of thereaction. Preferably, the target gene product can be anchored onto asolid surface, and the test compound, (which is not anchored), can belabeled, either directly or indirectly, with detectable labels discussedherein.

[0588] It may be desirable to immobilize either 27877, 18080, 14081,32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577, an anti-27877,18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577antibody or its target molecule to facilitate separation of complexedfrom uncomplexed forms of one or both of the proteins, as well as toaccommodate automation of the assay. Binding of a test compound to a27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or65577 protein, or interaction of a 27877, 18080, 14081, 32140, 50352,16658, 14223, 16002, 50566, 65552 or 65577 protein with a targetmolecule in the presence and absence of a candidate compound, can beaccomplished in any vessel suitable for containing the reactants.Examples of such vessels include microtiter plates, test tubes, andmicro-centrifuge tubes. In one embodiment, a fusion protein can beprovided which adds a domain that allows one or both of the proteins tobe bound to a matrix. For example, glutathione-S-transferase/27877,18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577fusion proteins or glutathione-S-transferase/target fusion proteins canbe adsorbed onto glutathione sepharose beads (Sigma Chemical, St. Louis,Mo.) or glutathione derivatized microtiter plates, which are thencombined with the test compound or the test compound and either thenon-adsorbed target protein or 27877, 18080, 14081, 32140, 50352, 16658,14223, 16002, 50566, 65552 or 65577 protein, and the mixture incubatedunder conditions conducive to complex formation (e.g., at physiologicalconditions for salt and pH).

[0589] Following incubation, the beads or microtiter plate wells arewashed to remove any unbound components, the matrix immobilized in thecase of beads, complex determined either directly or indirectly, forexample, as described above. Alternatively, the complexes can bedissociated from the matrix, and the level of 27877, 18080, 14081,32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 binding oractivity determined using standard techniques.

[0590] Other techniques for immobilizing either a 27877, 18080, 14081,32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 protein or atarget molecule on matrices include using conjugation of biotin andstreptavidin. Biotinylated 27877, 18080, 14081, 32140, 50352, 16658,14223, 16002, 50566, 65552 or 65577 protein or target molecules can beprepared from biotin-NHS (N-hydroxy-succinimide) using techniques knownin the art (e.g., biotinylation kit, Pierce Chemicals, Rockford, Ill.),and immobilized in the wells of streptavidin-coated 96 well plates(Pierce Chemical).

[0591] In order to conduct the assay, the non-immobilized component isadded to the coated surface containing the anchored component. After thereaction is complete, unreacted components are removed (e.g., bywashing) under conditions such that any complexes formed will remainimmobilized on the solid surface. The detection of complexes anchored onthe solid surface can be accomplished in a number of ways. Where thepreviously non-immobilized component is pre-labeled, the detection oflabel immobilized on the surface indicates that complexes were formed.Where the previously non-immobilized component is not pre-labeled, anindirect label can be used to detect complexes anchored on the surface;e.g., using a labeled antibody specific or selective for the immobilizedcomponent (the antibody, in turn, can be directly labeled or indirectlylabeled with, e.g., a labeled anti-Ig antibody).

[0592] In one embodiment, this assay is performed utilizing antibodiesreactive with 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577 protein or target molecules but which do notinterfere with binding of the 27877, 18080, 14081, 32140, 50352, 16658,14223, 16002, 50566, 65552 or 65577 protein to its target molecule. Suchantibodies can be derivatized to the wells of the plate, and unboundtarget or 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566,65552 or 65577 protein trapped in the wells by antibody conjugation.Methods for detecting such complexes, in addition to those describedabove for the GST-immobilized complexes, include immunodetection ofcomplexes using antibodies reactive with the 27877, 18080, 14081, 32140,50352, 16658, 14223, 16002, 50566, 65552 or 65577 protein or targetmolecule, as well as enzyme-linked assays which rely on detecting anenzymatic activity associated with the 27877, 18080, 14081, 32140,50352, 16658, 14223, 16002, 50566, 65552 or 65577 protein or targetmolecule.

[0593] Alternatively, cell free assays can be conducted in a liquidphase. In such an assay, the reaction products are separated fromunreacted components, by any of a number of standard techniques,including but not limited to: differential centrifugation (see, forexample, Rivas and Minton (1993) Trends Biochem Sci 18:284-7);chromatography (gel filtration chromatography, ion-exchangechromatography); electrophoresis (see, e.g., Ausubel et al., eds. (1999)Current Protocols in Molecular Biology, J. Wiley, New York.); andimmunoprecipitation (see, for example, Ausubel et al., eds. (1999)Current Protocols in Molecular Biology, J. Wiley, New York). Such resinsand chromatographic techniques are known to one skilled in the art (see,e.g., Heegaard (1998) J Mol Recognit 11: 141-8; Hage and Tweed (1997) JChromatogr B Biomed Sci Appl. 699:499-525). Further, fluorescence energytransfer can also be conveniently utilized, as described herein, todetect binding without further purification of the complex fromsolution.

[0594] In a preferred embodiment, the assay includes contacting the27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or65577 protein or biologically active portion thereof with a knowncompound which binds 27877, 18080, 14081, 32140, 50352, 16658, 14223,16002, 50566, 65552 or 65577 to form an assay mixture, contacting theassay mixture with a test compound, and determining the ability of thetest compound to interact with a 27877, 18080, 14081, 32140, 50352,16658, 14223, 16002, 50566, 65552 or 65577 protein, wherein determiningthe ability of the test compound to interact with a 27877, 18080, 14081,32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 proteinincludes determining the ability of the test compound to preferentiallybind to 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566,65552 or 65577 or biologically active portion thereof, or to modulatethe activity of a target molecule, as compared to the known compound.

[0595] The target gene products of the invention can, in vivo, interactwith one or more cellular or extracellular macromolecules, such asproteins. For the purposes of this discussion, such cellular andextracellular macromolecules are referred to herein as “bindingpartners.” Compounds that disrupt such interactions can be useful inregulating the activity of the target gene product. Such compounds caninclude, but are not limited to molecules such as antibodies, peptides,and small molecules. The preferred target genes/products for use in thisembodiment are the 27877, 18080, 14081, 32140, 50352, 16658, 14223,16002, 50566, 65552 or 65577 genes herein identified. In an alternativeembodiment, the invention provides methods for determining the abilityof the test compound to modulate the activity of a 27877, 18080, 14081,32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 protein throughmodulation of the activity of a downstream effector of a 27877, 18080,14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552, 65577 or 56919target molecule. For example, the activity of the effector molecule onan appropriate target can be determined, or the binding of the effectorto an appropriate target can be determined, as previously described.

[0596] To identify compounds that interfere with the interaction betweenthe target gene product and its cellular or extracellular bindingpartner(s), a reaction mixture containing the target gene product andthe binding partner is prepared, under conditions and for a timesufficient, to allow the two products to form complex. In order to testan inhibitory agent, the reaction mixture is provided in the presenceand absence of the test compound. The test compound can be initiallyincluded in the reaction mixture, or can be added at a time subsequentto the addition of the target gene and its cellular or extracellularbinding partner. Control reaction mixtures are incubated without thetest compound or with a placebo. The formation of any complexes betweenthe target gene product and the cellular or extracellular bindingpartner is then detected. The formation of a complex in the controlreaction, but not in the reaction mixture containing the test compound,indicates that the compound interferes with the interaction of thetarget gene product and the interactive binding partner.

[0597] Additionally, complex formation within reaction mixturescontaining the test compound and normal target gene product can also becompared to complex formation within reaction mixtures containing thetest compound and mutant target gene product. This comparison can beimportant in those cases wherein it is desirable to identify compoundsthat disrupt interactions of mutant but not normal target gene products.

[0598] These assays can be conducted in a heterogeneous or homogeneousformat. Heterogeneous assays involve anchoring either the target geneproduct or the binding partner onto a solid phase, and detectingcomplexes anchored on the solid phase at the end of the reaction. Inhomogeneous assays, the entire reaction is carried out in a liquidphase. In either approach, the order of addition of reactants can bevaried to obtain different information about the compounds being tested.For example, test compounds that interfere with the interaction betweenthe target gene products and the binding partners, e.g., by competition,can be identified by conducting the reaction in the presence of the testsubstance. Alternatively, test compounds that disrupt preformedcomplexes, e.g., compounds with higher binding constants that displaceone of the components from the complex, can be tested by adding the testcompound to the reaction mixture after complexes have been formed. Thevarious formats are briefly described below.

[0599] In a heterogeneous assay system, either the target gene productor the interactive cellular or extracellular binding partner, isanchored onto a solid surface (e.g., a microtiter plate), while thenon-anchored species is labeled, either directly or indirectly. Theanchored species can be immobilized by non-covalent or covalentattachments. Alternatively, an immobilized antibody specific orselective for the species to be anchored can be used to anchor thespecies to the solid surface.

[0600] In order to conduct the assay, the partner of the immobilizedspecies is exposed to the coated surface with or without the testcompound. After the reaction is complete, unreacted components areremoved (e.g., by washing) and any complexes formed will remainimmobilized on the solid surface. Where the non-immobilized species ispre-labeled, the detection of label immobilized on the surface indicatesthat complexes were formed. Where the non-immobilized species is notpre-labeled, an indirect label can be used to detect complexes anchoredon the surface; e.g., using a labeled antibody specific or selective forthe initially non-immobilized species (the antibody, in turn, can bedirectly labeled or indirectly labeled with, e.g., a labeled anti-Igantibody). Depending upon the order of addition of reaction components,test compounds that inhibit complex formation or that disrupt preformedcomplexes can be detected.

[0601] Alternatively, the reaction can be conducted in a liquid phase inthe presence or absence of the test compound, the reaction productsseparated from unreacted components, and complexes detected; e.g., usingan immobilized antibody specific or selective for one of the bindingcomponents to anchor any complexes formed in solution, and a labeledantibody specific or selective for the other partner to detect anchoredcomplexes. Again, depending upon the order of addition of reactants tothe liquid phase, test compounds that inhibit complex or that disruptpreformed complexes can be identified.

[0602] In an alternate embodiment of the invention, a homogeneous assaycan be used. For example, a preformed complex of the target gene productand the interactive cellular or extracellular binding partner product isprepared in that either the target gene products or their bindingpartners are labeled, but the signal generated by the label is quencheddue to complex formation (see, e.g., U.S. Pat. No. 4,109,496 thatutilizes this approach for immunoassays). The addition of a testsubstance that competes with and displaces one of the species from thepreformed complex will result in the generation of a signal abovebackground. In this way, test substances that disrupt target geneproduct-binding partner interaction can be identified.

[0603] In yet another aspect, the 27877, 18080, 14081, 32140, 50352,16658, 14223, 16002, 50566, 65552 or 65577 proteins can be used as “baitproteins” in a two-hybrid assay or three-hybrid assay (see, e.g., U.S.Pat. No. 5,283,317; Zervos et al. (1993) Cell 72:223-232; Madura et al.(1993) J. Biol. Chem. 268:12046-12054; Bartel et al. (1993)Biotechniques 14:920-924; Iwabuchi et al. (1993) Oncogene 8:1693-1696;and Brent WO94/10300), to identify other proteins, which bind to orinteract with 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577 (“27877, 18080, 14081, 32140, 50352, 16658, 14223,16002, 50566, 65552 or 65577-binding proteins” or “27877, 18080, 14081,32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577-bp”) and areinvolved in 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577 activity. Such 27877, 18080, 14081, 32140, 50352,16658, 14223, 16002, 50566, 65552 or 65577-bps can be activators orinhibitors of signals by the 27877, 18080, 14081, 32140, 50352, 16658,14223, 16002, 50566, 65552 or 65577 proteins or 27877, 18080, 14081,32140, 50352, 16658, 14223, 16002, 50566, 65552, 65577 or 56919 targetsas, for example, downstream elements of a 27877, 18080, 14081, 32140,50352, 16658, 14223, 16002, 50566, 65552 or 65577-mediated signalingpathway.

[0604] The two-hybrid system is based on the modular nature of mosttranscription factors, which consist of separable DNA-binding andactivation domains. Briefly, the assay utilizes two different DNAconstructs. In one construct, the gene that codes for a 27877, 18080,14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 proteinis fused to a gene encoding the DNA binding domain of a knowntranscription factor (e.g., GAL-4). In the other construct, a DNAsequence, from a library of DNA sequences, that encodes an unidentifiedprotein (“prey” or “sample”) is fused to a gene that codes for theactivation domain of the known transcription factor. (Alternatively the:27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or65577 protein can be the fused to the activator domain.) If the “bait”and the “prey” proteins are able to interact, in vivo, forming a 27877,18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or65577-dependent complex, the DNA-binding and activation domains of thetranscription factor are brought into close proximity. This proximityallows transcription of a reporter gene (e.g., lacZ) which is operablylinked to a transcriptional regulatory site responsive to thetranscription factor. Expression of the reporter gene can be detectedand cell colonies containing the functional transcription factor can beisolated and used to obtain the cloned gene which encodes the proteinwhich interacts with the 27877, 18080, 14081, 32140, 50352, 16658,14223, 16002, 50566, 65552 or 65577 protein.

[0605] In another embodiment, modulators of 27877, 18080, 14081, 32140,50352, 16658, 14223, 16002, 50566, 65552 or 65577 expression areidentified. For example, a cell or cell free mixture is contacted with acandidate compound and the expression of 27877, 18080, 14081, 32140,50352, 16658, 14223, 16002, 50566, 65552 or 65577 mRNA or proteinevaluated relative to the level of expression of 27877, 18080, 14081,32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 mRNA or proteinin the absence of the candidate compound. When expression of 27877,18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577mRNA or protein is greater in the presence of the candidate compoundthan in its absence, the candidate compound is identified as astimulator of 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577 mRNA or protein expression. Alternatively, whenexpression of 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577 mRNA or protein is less (statisticallysignificantly less) in the presence of the candidate compound than inits absence, the candidate compound is identified as an inhibitor of27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or65577 mRNA or protein expression. The level of 27877, 18080, 14081,32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 mRNA or proteinexpression can be determined by methods described herein for detecting27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or65577 mRNA or protein.

[0606] In another aspect, the invention pertains to a combination of twoor more of the assays described herein. For example, a modulating agentcan be identified using a cell-based or a cell free assay, and theability of the agent to modulate the activity of a 27877, 18080, 14081,32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 protein can beconfirmed in vivo, e.g., in an animal such as an animal model foraberrant or deficient phospholipase activity, serine carboxypeptidaseactivity, trypsin-like serine protease activity, aldehyde dehydrogenaseactivity, ubiquitin-protein ligase activity, protein kinase activity,hydrolase activity or matrix metalloproteinase activity.

[0607] This invention further pertains to novel agents identified by theabove-described screening assays. Accordingly, it is within the scope ofthis invention to further use an agent identified as described herein(e.g., a 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566,65552 or 65577 modulating agent, an antisense 27877, 18080, 14081,32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 nucleic acidmolecule, a 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577-specific antibody, or a 27877, 18080, 14081,32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577-bindingpartner) in an appropriate animal model to determine the efficacy,toxicity, side effects, or mechanism of action, of treatment with suchan agent. Furthermore, novel agents identified by the above-describedscreening assays can be used for treatments as described herein.

[0608] Detection Assays

[0609] Portions or fragments of the nucleic acid sequences identifiedherein can be used as polynucleotide reagents. For example, thesesequences can be used to: (i) map their respective genes on a chromosomee.g., to locate gene regions associated with genetic disease or toassociate 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566,65552 or 65577 with a disease; (ii) identify an individual from a minutebiological sample (tissue typing); and (iii) aid in forensicidentification of a biological sample. These applications are describedin the subsections below.

[0610] Chromosome Mapping

[0611] The 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577 nucleotide sequences or portions thereof can beused to map the location of the 27877, 18080, 14081, 32140, 50352,16658, 14223, 16002, 50566, 65552 or 65577 genes on a chromosome. Thisprocess is called chromosome mapping. Chromosome mapping is useful incorrelating the 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577 sequences with genes associated with disease.

[0612] Briefly, 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577 genes can be mapped to chromosomes by preparingPCR primers (preferably 15-25 bp in length) from the 27877, 18080,14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577nucleotide sequences. These primers can then be used for PCR screeningof somatic cell hybrids containing individual human chromosomes. Onlythose hybrids containing the human gene corresponding to the 27877,18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577sequences will yield an amplified fragment.

[0613] A panel of somatic cell hybrids in which each cell line containseither a single human chromosome or a small number of human chromosomes,and a full set of mouse chromosomes, can allow easy mapping ofindividual genes to specific human chromosomes. (D'Eustachio et al.(1983) Science 220:919-924).

[0614] Other mapping strategies e.g., in situ hybridization (describedin Fan et al. (1990) Proc. Natl. Acad. Sci. USA, 87:6223-27),pre-screening with labeled flow-sorted chromosomes, and pre-selection byhybridization to chromosome specific cDNA libraries can be used to map27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or65577 to a chromosomal location.

[0615] Fluorescence in situ hybridization (FISH) of a DNA sequence to ametaphase chromosomal spread can further be used to provide a precisechromosomal location in one step. The FISH technique can be used with aDNA sequence as short as 500 or 600 bases. However, clones larger than1,000 bases have a higher likelihood of binding to a unique chromosomallocation with sufficient signal intensity for simple detection.Preferably 1,000 bases, and more preferably 2,000 bases will suffice toget good results at a reasonable amount of time. For a review of thistechnique, see Verma et al. (1988) Human Chromosomes: A Manual of BasicTechniques, Pergamon Press, New York).

[0616] Reagents for chromosome mapping can be used individually to marka single chromosome or a single site on that chromosome, or panels ofreagents can be used for marking multiple sites and/or multiplechromosomes. Reagents corresponding to noncoding regions of the genesactually are preferred for mapping purposes. Coding sequences are morelikely to be conserved within gene families, thus increasing the chanceof cross hybridizations during chromosomal mapping.

[0617] Once a sequence has been mapped to a precise chromosomallocation, the physical position of the sequence on the chromosome can becorrelated with genetic map data. (Such data are found, for example, inMcKusick, Mendelian Inheritance in Man, available on-line through JohnsHopkins University Welch Medical Library). The relationship between agene and a disease, mapped to the same chromosomal region, can then beidentified through linkage analysis (co-inheritance of physicallyadjacent genes), described in, for example, Egeland et al. (1987)Nature, 325:783-787.

[0618] Moreover, differences in the DNA sequences between individualsaffected and unaffected with a disease associated with the 27877, 18080,14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 gene,can be determined. If a mutation is observed in some or all of theaffected individuals but not in any unaffected individuals, then themutation is likely to be the causative agent of the particular disease.Comparison of affected and unaffected individuals generally involvesfirst looking for structural alterations in the chromosomes, such asdeletions or translocations that are visible from chromosome spreads ordetectable using PCR based on that DNA sequence. Ultimately, completesequencing of genes from several individuals can be performed to confirmthe presence of a mutation and to distinguish mutations frompolymorphisms.

[0619] Tissue Typing

[0620] 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566,65552 or 65577 sequences can be used to identify individuals frombiological samples using, e.g., restriction fragment length polymorphism(RFLP). In this technique, an individual's genomic DNA is digested withone or more restriction enzymes, the fragments separated, e.g., in aSouthern blot, and probed to yield bands for identification. Thesequences of the present invention are useful as additional DNA markersfor RFLP (described in U.S. Pat. No. 5,272,057).

[0621] Furthermore, the sequences of the present invention can also beused to determine the actual base-by-base DNA sequence of selectedportions of an individual's genome. Thus, the 27877, 18080, 14081,32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 nucleotidesequences described herein can be used to prepare two PCR primers fromthe 5′ and 3′ ends of the sequences. These primers can then be used toamplify an individual's DNA and subsequently sequence it. Panels ofcorresponding DNA sequences from individuals, prepared in this manner,can provide unique individual identifications, as each individual willhave a unique set of such DNA sequences due to allelic differences.

[0622] Allelic variation occurs to some degree in the coding regions ofthese sequences, and to a greater degree in the noncoding regions. Eachof the sequences described herein can, to some degree, be used as astandard against which DNA from an individual can be compared foridentification purposes. Because greater numbers of polymorphisms occurin the noncoding regions, fewer sequences are necessary to differentiateindividuals. The noncoding sequences of SEQ ID NO: 1, 4, 11, 20, 25, 29,35, 38, 41, 73, 76 or 86 can provide positive individual identificationwith a panel of perhaps 10 to 1,000 primers which each yield a noncodingamplified sequence of 100 bases. If predicted coding sequences, such asthose in SEQ ID NO: 3, 6, 13, 22, 27, 31, 37, 40, 43, 75, 78 or 88 areused, a more appropriate number of primers for positive individualidentification would be 500-2,000.

[0623] If a panel of reagents from 27877, 18080, 14081, 32140, 50352,16658, 14223, 16002, 50566, 65552 or 65577 nucleotide sequencesdescribed herein is used to generate a unique identification databasefor an individual, those same reagents can later be used to identifytissue from that individual. Using the unique identification database,positive identification of the individual, living or dead, can be madefrom extremely small tissue samples.

[0624] Use of Partial 27877, 18080, 14081, 32140, 50352, 16658, 14223,16002, 50566, 65552 or 65577 Sequences in Forensic Biology

[0625] DNA-based identification techniques can also be used in forensicbiology. To make such an identification, PCR technology can be used toamplify DNA sequences taken from very small biological samples such astissues, e.g., hair or skin, or body fluids, e.g., blood, saliva, orsemen found at a crime scene. The amplified sequence can then becompared to a standard, thereby allowing identification of the origin ofthe biological sample.

[0626] The sequences of the present invention can be used to providepolynucleotide reagents, e.g., PCR primers, targeted to specific loci inthe human genome, which can enhance the reliability of DNA-basedforensic identifications by, for example, providing another“identification marker” (i.e. another DNA sequence that is unique to aparticular individual). As mentioned above, actual base sequenceinformation can be used for identification as an accurate alternative topatterns formed by restriction enzyme generated fragments. Sequencestargeted to noncoding regions of SEQ ID NO: 1, 4, 11, 20, 25, 29, 35,38, 41, 73, 76 or 86 (e.g., fragments derived from the noncoding regionsof SEQ ID NO: 1, 4, 11, 20, 25, 29, 35, 38, 41, 73, 76 or 86 having alength of at least 20 bases, preferably at least 30 bases) areparticularly appropriate for this use.

[0627] The 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577 nucleotide sequences described herein can furtherbe used to provide polynucleotide reagents, e.g., labeled or labelableprobes which can be used in, for example, an in situ hybridizationtechnique, to identify a specific tissue. This can be very useful incases where a forensic pathologist is presented with a tissue of unknownorigin. Panels of such 27877, 18080, 14081, 32140, 50352, 16658, 14223,16002, 50566, 65552 or 65577 probes can be used to identify tissue byspecies and/or by organ type.

[0628] In a similar fashion, these reagents, e.g., 27877, 18080, 14081,32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 primers orprobes can be used to screen tissue culture for contamination (i.e.screen for the presence of a mixture of different types of cells in aculture).

[0629] Predictive Medicine

[0630] The present invention also pertains to the field of predictivemedicine in which diagnostic assays, prognostic assays, and monitoringclinical trials are used for prognostic (predictive) purposes to therebytreat an individual.

[0631] Generally, the invention provides, a method of determining if asubject is at risk for a disorder related to a lesion in or themisexpression of a gene which encodes 27877, 18080, 14081, 32140, 50352,16658, 14223, 16002, 50566, 65552 or 65577.

[0632] Such disorders include, e.g., a disorder associated with themisexpression of 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577 gene; a cellular proliferative and/ordifferentiative disorder, brain, blood vessel, platelet, breast, colon,kidney, lung, ovarian, prostate, hematopoeitic, pancreatic, skeletalmuscle, testicular, skin, hormonal, associated with bone metabolism,immune e.g., inflammatory, cardiovascular, endothelial cell, liver,viral diseases, pain, metabolic, anemias, angiogenesis, neoplastic,endocrine, neurological or heart disorder.

[0633] The method includes one or more of the following: detecting, in atissue of the subject, the presence or absence of a mutation whichaffects the expression of the 27877, 18080, 14081, 32140, 50352, 16658,14223, 16002, 50566, 65552 or 65577 gene, or detecting the presence orabsence of a mutation in a region which controls the expression of thegene, e.g., a mutation in the 5′ control region; detecting, in a tissueof the subject, the presence or absence of a mutation which alters thestructure of the 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577 gene; detecting, in a tissue of the subject, themisexpression of the 27877, 18080, 14081, 32140, 50352, 16658, 14223,16002, 50566, 65552 or 65577 gene, at the mRNA level, e.g., detecting anon-wild type level of an mRNA; or detecting, in a tissue of thesubject, the misexpression of the gene, at the protein level, e.g.,detecting a non-wild type level of a 27877, 18080, 14081, 32140, 50352,16658, 14223, 16002, 50566, 65552 or 65577 polypeptide.

[0634] In preferred embodiments the method includes: ascertaining theexistence of at least one of: a deletion of one or more nucleotides fromthe 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552or 65577 gene; an insertion of one or more nucleotides into the gene, apoint mutation, e.g., a substitution of one or more nucleotides of thegene, a gross chromosomal rearrangement of the gene, e.g., atranslocation, inversion, or deletion.

[0635] For example, detecting the genetic lesion can include: (i)providing a probe/primer including an oligonucleotide containing aregion of nucleotide sequence which hybridizes to a sense or antisensesequence from SEQ ID NO: 1, 4, 11, 20, 25, 29, 35, 38, 41, 73, 76 or 86,or naturally occurring mutants thereof or 5′ or 3′ flanking sequencesnaturally associated with the 27877, 18080, 14081, 32140, 50352, 16658,14223, 16002, 50566, 65552 or 65577 gene; (ii) exposing the probe/primerto nucleic acid of the tissue; and detecting, by hybridization, e.g., insitu hybridization, of the probe/primer to the nucleic acid, thepresence or absence of the genetic lesion.

[0636] In preferred embodiments detecting the misexpression includesascertaining the existence of at least one of: an alteration in thelevel of a messenger RNA transcript of the 27877, 18080, 14081, 32140,50352, 16658, 14223, 16002, 50566, 65552 or 65577 gene; the presence ofa non-wild type splicing pattern of a messenger RNA transcript of thegene; or a non-wild type level of 27877, 18080, 14081, 32140, 50352,16658, 14223, 16002, 50566, 65552 or 65577.

[0637] Methods of the invention can be used prenatally or to determineif a subject's offspring will be at risk for a disorder.

[0638] In preferred embodiments the method includes determining thestructure of a 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577 gene, an abnormal structure being indicative ofrisk for the disorder.

[0639] In preferred embodiments the method includes contacting a samplefrom the subject with an antibody to the 27877, 18080, 14081, 32140,50352, 16658, 14223, 16002, 50566, 65552 or 65577 protein or a nucleicacid, which hybridizes specifically with the gene. These and otherembodiments are discussed below.

[0640] Diagnostic and Prognostic Assays

[0641] The presence, level, or absence of 27877, 18080, 14081, 32140,50352, 16658, 14223, 16002, 50566, 65552 or 65577 protein or nucleicacid in a biological sample can be evaluated by obtaining a biologicalsample from a test subject and contacting the biological sample with acompound or an agent capable of detecting 27877, 18080, 14081, 32140,50352, 16658, 14223, 16002, 50566, 65552 or 65577 protein or nucleicacid (e.g., mRNA, genomic DNA) that encodes 27877, 18080, 14081, 32140,50352, 16658, 14223, 16002, 50566, 65552 or 65577 protein such that thepresence of 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577 protein or nucleic acid is detected in thebiological sample. The term “biological sample” includes tissues, cellsand biological fluids isolated from a subject, as well as tissues, cellsand fluids present within a subject. A preferred biological sample isserum. The level of expression of the 27877, 18080, 14081, 32140, 50352,16658, 14223, 16002, 50566, 65552 or 65577 gene can be measured in anumber of ways, including, but not limited to: measuring the mRNAencoded by the 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577 genes; measuring the amount of protein encoded bythe 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552or 65577 genes; or measuring the activity of the protein encoded by the27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or65577 genes.

[0642] The level of mRNA corresponding to the 27877, 18080, 14081,32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 gene in a cellcan be determined both by in situ and by in vitro formats.

[0643] The isolated mRNA can be used in hybridization or amplificationassays that include, but are not limited to, Southern or Northernanalyses, polymerase chain reaction analyses and probe arrays. Onepreferred diagnostic method for the detection of mRNA levels involvescontacting the isolated mRNA with a nucleic acid molecule (probe) thatcan hybridize to the mRNA encoded by the gene being detected. Thenucleic acid probe can be, for example, a full-length 27877, 18080,14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 nucleicacid, such as the nucleic acid of SEQ ID NO: 1, 4, 11, 20, 25, 29, 35,38, 41, 73, 76 or -86, or a portion thereof, such as an oligonucleotideof at least 7, 15, 30, 50, 100, 250 or 500 nucleotides in length andsufficient to specifically hybridize under stringent conditions to27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or65577 mRNA or genomic DNA. Other suitable probes for use in thediagnostic assays are described herein.

[0644] In one format, mRNA (or cDNA) is immobilized on a surface andcontacted with the probes, for example by running the isolated mRNA onan agarose gel and transferring the mRNA from the gel to a membrane,such as nitrocellulose. In an alternative format, the probes areimmobilized on a surface and the mRNA (or cDNA) is contacted with theprobes, for example, in a two-dimensional gene chip array. A skilledartisan can adapt known mRNA detection methods for use in detecting thelevel of mRNA encoded by the 27877, 18080, 14081, 32140, 50352, 16658,14223, 16002, 50566, 65552 or 65577 genes.

[0645] The level of mRNA in a sample that is encoded by one of 27877,18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577can be evaluated with nucleic acid amplification, e.g., by rtPCR (Mullis(1987) U.S. Pat. No. 4,683,202), ligase chain reaction (Barany (1991)Proc. Natl. Acad. Sci. USA 88:189-193), self sustained sequencereplication (Guatelli et al., (1990) Proc. Natl. Acad. Sci. USA87:1874-1878), transcriptional amplification system (Kwoh et al.,(1989), Proc. Natl. Acad. Sci. USA 86:1173-1177), Q-Beta Replicase(Lizardi et al., (1988) Bio/Technology 6:1197), rolling circlereplication (Lizardi et al., U.S. Pat. No. 5,854,033) or any othernucleic acid amplification method, followed by the detection of theamplified molecules using techniques known in the art. As used herein,amplification primers are defined as being a pair of nucleic acidmolecules that can anneal to 5′ or 3′ regions of a gene (plus and minusstrands., respectively, or vice-versa) and contain a short region inbetween. In general, amplification primers are from about 10 to 30nucleotides in length and flank a region from about 50 to 200nucleotides in length. Under appropriate conditions and with appropriatereagents, such primers permit the amplification of a nucleic acidmolecule comprising the nucleotide sequence flanked by the primers.

[0646] For in situ methods, a cell or tissue sample can beprepared/processed and immobilized on a support, typically a glassslide, and then contacted with a probe that can hybridize to mRNA thatencodes the 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577 gene being analyzed.

[0647] In another embodiment, the methods further contacting a controlsample with a compound or agent capable of detecting 27877, 18080,14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 mRNA, orgenomic DNA, and comparing the presence of 27877, 18080, 14081, 32140,50352, 16658, 14223, 16002, 50566, 65552 or 65577 mRNA or genomic DNA inthe control sample with the presence of 27877, 18080, 14081, 32140,50352, 16658, 14223, 16002, 50566, 65552 or 65577 mRNA or genomic DNA inthe test sample.

[0648] A variety of methods can be used to determine the level ofprotein encoded by 27877, 18080, 14081, 32140, 50352, 16658, 14223,16002, 50566, 65552 or 65577. In general, these methods includecontacting an agent that selectively binds to the protein, such as anantibody with a sample, to evaluate the level of protein in the sample.In a preferred embodiment, the antibody bears a detectable label.Antibodies can be polyclonal, or more preferably, monoclonal. An intactantibody, or a fragment thereof (e.g., Fab or F(ab′)₂) can be used. Theterm “labeled”, with regard to the probe or antibody, is intended toencompass direct labeling of the probe or antibody by coupling (i.e.,physically linking) a detectable substance to the probe or antibody, aswell as indirect labeling of the probe or antibody by reactivity with adetectable substance. Examples of detectable substances are providedherein.

[0649] The detection methods can be used to detect 27877, 18080, 14081,32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 protein in abiological sample in vitro as well as in vivo. In vitro techniques fordetection of 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577 protein include enzyme linked immunosorbent assays(ELISAs), immunoprecipitations, immunofluorescence, enzyme immunoassay(EIA), radioimmunoassay (RIA), and Western blot analysis. In vivotechniques for detection of 27877, 18080, 14081, 32140, 50352, 16658,14223, 16002, 50566, 65552 or 65577 protein include introducing into asubject a labeled anti-27877, 18080, 14081, 32140, 50352, 16658, 14223,16002, 50566, 65552 or 65577 antibody. For example, the antibody can belabeled with a radioactive marker whose presence and location in asubject can be detected by standard imaging techniques.

[0650] In another embodiment, the methods further include contacting thecontrol sample with a compound or agent capable of detecting 27877,18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577protein, and comparing the presence of 27877, 18080, 14081, 32140,50352, 16658, 14223, 16002, 50566, 65552 or 65577 protein in the controlsample with the presence of 27877, 18080, 14081, 32140, 50352, 16658,14223, 16002, 50566, 65552 or 65577 protein in the test sample.

[0651] The invention also includes kits for detecting the presence of27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or65577 in a biological sample. For example, the kit can include acompound or agent capable of detecting 27877, 18080, 14081, 32140,50352, 16658, 14223, 16002, 50566, 65552 or 65577 protein or mRNA in abiological sample; and a standard. The compound or agent can be packagedin a suitable container. The kit can further comprise instructions forusing the kit to detect 27877, 18080, 14081, 32140, 50352, 16658, 14223,16002, 50566, 65552 or 65577 protein or nucleic acid.

[0652] For antibody-based kits, the kit can include: (1) a firstantibody (e.g., attached to a solid support) which binds to apolypeptide corresponding to a marker of the invention; and, optionally,(2) a second, different antibody which binds to either the polypeptideor the first antibody and is conjugated to a detectable agent.

[0653] For oligonucleotide-based kits, the kit can include: (1) anoligonucleotide, e.g., a detectably labeled oligonucleotide, whichhybridizes to a nucleic acid sequence encoding a polypeptidecorresponding to a marker of the invention or (2) a pair of primersuseful for amplifying a nucleic acid molecule corresponding to a markerof the invention. The kit can also includes a buffering agent, apreservative, or a protein stabilizing agent. The kit can also includescomponents necessary for detecting the detectable agent (e.g., an enzymeor a substrate). The kit can also contain a control sample or a seriesof control samples which can be assayed and compared to the test samplecontained. Each component of the kit can be enclosed within anindividual container and all of the various containers can be within asingle package, along with instructions for interpreting the results ofthe assays performed using the kit.

[0654] The diagnostic methods described herein can identify subjectshaving, or at risk of developing, a disease or disorder associated withmisexpressed or aberrant or unwanted 27877, 18080, 14081, 32140, 50352,16658, 14223, 16002, 50566, 65552 or 65577 expression or activity. Asused herein, the term “unwanted” includes an unwanted phenomenoninvolved in a biological response such as pain or deregulated cellproliferation.

[0655] In one embodiment, a disease or disorder associated with aberrantor unwanted 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577 expression or activity is identified. A testsample is obtained from a subject and 27877, 18080, 14081, 32140, 50352,16658, 14223, 16002, 50566, 65552 or 65577 protein or nucleic acid(e.g., mRNA or genomic DNA) is evaluated, wherein the level, e.g., thepresence or absence, of 27877, 18080, 14081, 32140, 50352, 16658, 14223,16002, 50566, 65552 or 65577 protein or nucleic acid is diagnostic for asubject having or at risk of developing a disease or disorder associatedwith aberrant or unwanted 27877, 18080, 14081, 32140, 50352, 16658,14223, 16002, 50566, 65552 or 65577 expression or activity. As usedherein, a “test sample” refers to a biological sample obtained from asubject of interest, including a biological fluid (e.g., serum), cellsample, or tissue.

[0656] The prognostic assays described herein can be used to determinewhether a subject can be administered an agent (e.g., an agonist,antagonist, peptidomimetic, protein, peptide, nucleic acid, smallmolecule, or other drug candidate) to treat a disease or disorderassociated with aberrant or unwanted 27877, 18080, 14081, 32140, 50352,16658, 14223, 16002, 50566, 65552 or 65577 expression or activity. Forexample, such methods can be used to determine whether a subject can beeffectively treated with an agent for a cellular proliferative and/ordifferentiative disorder, brain, blood vessel, platelet, breast, colon,kidney, lung, ovarian, prostate, hematopoeitic, pancreatic, skeletalmuscle, testicular, skin, hormonal, associated with bone metabolism,immune e.g., inflammatory, cardiovascular, endothelial cell, liver,viral diseases, pain, metabolic, anemias, angiogenesis, neoplastic,endocrine, neurological or heart disorder.

[0657] The methods of the invention can also be used to detect geneticalterations in a 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577 gene, thereby determining if a subject with thealtered gene is at risk for a disorder characterized by misregulation in27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or65577 protein activity or nucleic acid expression, such as a cellularproliferative and/or differentiative disorder, brain, blood vessel,platelet, breast, colon, kidney, lung, ovarian, prostate, hematopoeitic,pancreatic, skeletal muscle, testicular, skin, hormonal, associated withbone metabolism, immune e.g., inflammatory, cardiovascular, endothelialcell, liver, viral diseases, pain, metabolic, anemias, angiogenesis,neoplastic, endocrine, neurological or heart disorder. In preferredembodiments, the methods include detecting, in a sample from thesubject, the presence or absence of a genetic alteration characterizedby at least one of an alteration affecting the integrity of a geneencoding a 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577-protein, or the mis-expression of the 27877,18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577gene. For example, such genetic alterations can be detected byascertaining the existence of at least one of 1) a deletion of one ormore nucleotides from a 27877, 18080, 14081, 32140, 50352, 16658, 14223,16002, 50566, 65552 or 65577 gene; 2) an addition of one or morenucleotides to a 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577 gene; 3) a substitution of one or more nucleotidesof a 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566,65552 or 65577 gene, 4) a chromosomal rearrangement of a 27877, 18080,14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 gene; 5)an alteration in the level of a messenger RNA transcript of a 27877,18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577gene, 6) aberrant modification of a 27877, 18080, 14081, 32140, 50352,16658, 14223, 16002, 50566, 65552 or 65577 gene, such as of themethylation pattern of the genomic DNA, 7) the presence of a non-wildtype splicing pattern of a messenger RNA transcript of a 27877, 18080,14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 gene, 8)a non-wild type level of a 27877, 18080, 14081, 32140, 50352, 16658,14223, 16002, 50566, 65552 or 65577-protein, 9) allelic loss of a 27877,18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577gene, and 10) inappropriate post-translational modification of a 27877,18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or65577-protein.

[0658] An alteration can be detected without a probe/primer in apolymerase chain reaction, such as anchor PCR or RACE PCR, or,alternatively, in a ligation chain reaction (LCR), the latter of whichcan be particularly useful for detecting point mutations in the 27877,18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or65577-gene. This method can include the steps of collecting a sample ofcells from a subject, isolating nucleic acid (e.g., genomic, mRNA orboth) from the sample, contacting the nucleic acid sample with one ormore primers which specifically hybridize to a 27877, 18080, 14081,32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 gene underconditions such that hybridization and amplification of the 27877,18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577gene (if present) occurs, and detecting the presence or absence of anamplification product, or detecting the size of the amplificationproduct and comparing the length to a control sample. It is anticipatedthat PCR and/or LCR may be desirable to use as a preliminaryamplification step in conjunction with any of the techniques used fordetecting mutations described herein. Alternatively, other amplificationmethods described herein or known in the art can be used.

[0659] In another embodiment, mutations in a 27877, 18080, 14081, 32140,50352, 16658, 14223, 16002, 50566, 65552 or 65577 gene from a samplecell can be identified by detecting alterations in restriction enzymecleavage patterns. For example, sample and control DNA is isolated,amplified (optionally), digested with one or more restrictionendonucleases, and fragment length sizes are determined, e.g., by gelelectrophoresis and compared. Differences in fragment length sizesbetween sample and control DNA indicates mutations in the sample DNA.Moreover, the use of sequence specific ribozymes (see, for example, U.S.Pat. No. 5,498,531) can be used to score for the presence of specificmutations by development or loss of a ribozyme cleavage site.

[0660] In other embodiments, genetic mutations in 27877, 18080, 14081,32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 can beidentified by hybridizing a sample and control nucleic acids, e.g., DNAor RNA, two dimensional arrays, e.g., chip based arrays. Such arraysinclude a plurality of addresses, each of which is positionallydistinguishable from the other. A different probe is located at eachaddress of the plurality. The arrays can have a high density ofaddresses, e.g., can contain hundreds or thousands of oligonucleotidesprobes (Cronin et al. (1996) Human Mutation 7: 244-255; Kozal et al.(1996) Nature Medicine 2: 753-759). For example, genetic mutations in27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or65577 can be identified in two dimensional arrays containinglight-generated DNA probes as described in Cronin, M. T. et al. supra.Briefly, a first hybridization array of probes can be used to scanthrough long stretches of DNA in a sample and control to identify basechanges between the sequences by making linear arrays of sequentialoverlapping probes. This step allows the identification of pointmutations. This step is followed by a second hybridization array thatallows the characterization of specific mutations by using smaller,specialized probe arrays complementary to all variants or mutationsdetected. Each mutation array is composed of parallel probe sets, onecomplementary to the wild-type gene and the other complementary to themutant gene.

[0661] In yet another embodiment, any of a variety of sequencingreactions known in the art can be used to directly sequence the 27877,18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577gene and detect mutations by comparing the sequence of the sample 27877,18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577with the corresponding wild-type (control) sequence. Automatedsequencing procedures can be utilized when performing the diagnosticassays (Naeve et al. (1995) Biotechniques 19:448-53), includingsequencing by mass spectrometry.

[0662] Other methods for detecting mutations in the 27877, 18080, 14081,32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 gene includemethods in which protection from cleavage agents is used to detectmismatched bases in RNA/RNA or RNA/DNA heteroduplexes (Myers et al.(1985) Science 230:1242; Cotton et al. (1988) Proc. Natl Acad Sci USA85:4397; Saleeba et al. (1992) Methods Enzymol. 217:286-295).

[0663] In still another embodiment, the mismatch cleavage reactionemploys one or more proteins that recognize mismatched base pairs indouble-stranded DNA (so called “DNA mismatch repair” enzymes) in definedsystems for detecting and mapping point mutations in 27877, 18080,14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 cDNAsobtained from samples of cells. For example, the mutY enzyme of E. colicleaves A at G/A mismatches and the thymidine DNA glycosylase from HeLacells cleaves T at G/T mismatches (Hsu et al. (1994) Carcinogenesis15:1657-1662; U.S. Pat. No. 5,459,039).

[0664] In other embodiments, alterations in electrophoretic mobilitywill be used to identify mutations in 27877, 18080, 14081, 32140, 50352,16658, 14223, 16002, 50566, 65552 or 65577 genes. For example, singlestrand conformation polymorphism (SSCP) can be used to detectdifferences in electrophoretic mobility between mutant and wild typenucleic acids (Orita et al. (1989) Proc Natl. Acad. Sci USA: 86:2766,see also Cotton (1993) Mutat. Res. 285:125-144; and Hayashi (1992)Genet. Anal. Tech. Appl. 9:73-79). Single-stranded DNA fragments ofsample and control 27877, 18080, 14081, 32140, 50352, 16658, 14223,16002, 50566, 65552 or 65577 nucleic acids will be denatured and allowedto renature. The secondary structure of single-stranded nucleic acidsvaries according to sequence, the resulting alteration inelectrophoretic mobility enables the detection of even a single basechange. The DNA fragments can be labeled or detected with labeledprobes. The sensitivity of the assay can be enhanced by using RNA(rather than DNA), in which the secondary structure is more sensitive toa change in sequence. In a preferred embodiment, the subject methodutilizes heteroduplex analysis to separate double stranded heteroduplexmolecules on the basis of changes in electrophoretic mobility (Keen etal. (1991) Trends Genet 7:5).

[0665] In yet another embodiment, the movement of mutant or wild-typefragments in polyacrylamide gels containing a gradient of denaturant isassayed using denaturing gradient gel electrophoresis (DGGE) (Myers etal. (1985) Nature 313:495). When DGGE is used as the method of analysis,DNA will be modified to insure that it does not completely denature, forexample by adding a GC clamp of approximately 40 bp of high-meltingGC-rich DNA by PCR. In a further embodiment, a temperature gradient isused in place of a denaturing gradient to identify differences in themobility of control and sample DNA (Rosenbaum and Reissner (1987)Biophys Chem 265:12753).

[0666] Examples of other techniques for detecting point mutationsinclude, but are not limited to, selective oligonucleotidehybridization, selective amplification, or selective primer extension(Saiki et al. (1986) Nature 324:163); Saiki et al. (1989) Proc. NatlAcad. Sci USA 86:6230).

[0667] Alternatively, allele specific amplification technology whichdepends on selective PCR amplification can be used in conjunction withthe instant invention. Oligonucleotides used as primers for specificamplification can carry the mutation of interest in the center of themolecule (so that amplification depends on differential hybridization)(Gibbs et al. (1989) Nucleic Acids Res. 17:2437-2448) or at the extreme3′ end of one primer where, under appropriate conditions, mismatch canprevent, or reduce polymerase extension (Prossner (1993) Tibtech11:238). In addition it may be desirable to introduce a novelrestriction site in the region of the mutation to create cleavage-baseddetection (Gasparini et al. (1992) Mol. Cell Probes 6:1). It isanticipated that in certain embodiments amplification can also beperformed using Taq ligase for amplification (Barany (1991) Proc. Natl.Acad. Sci USA 88:189-93). In such cases, ligation will occur only ifthere is a perfect match at the 3′ end of the 5′ sequence making itpossible to detect the presence of a known mutation at a specific siteby looking for the presence or absence of amplification.

[0668] The methods described herein can be performed, for example, byutilizing pre-packaged diagnostic kits comprising at least one probenucleic acid or antibody reagent described herein, which can beconveniently used, e.g., in clinical settings to diagnose patientsexhibiting symptoms or family history of a disease or illness involvinga 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552or 65577 gene.

[0669] Use of 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577 Molecules as Surrogate Markers

[0670] The 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577 molecules of the invention are also useful asmarkers of disorders or disease states, as markers for precursors ofdisease states, as markers for predisposition of disease states, asmarkers of drug activity, or as markers of the pharmacogenomic profileof a subject. Using the methods described herein, the presence, absenceand/or quantity of the 27877, 18080, 14081, 32140, 50352, 16658, 14223,16002, 50566, 65552 or 65577 molecules of the invention can be detected,and can be correlated with one or more biological states in vivo. Forexample, the 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577 molecules of the invention can serve as surrogatemarkers for one or more disorders or disease states or for conditionsleading up to disease states. As used herein, a “surrogate marker” is anobjective biochemical marker which correlates with the absence orpresence of a disease or disorder, or with the progression of a diseaseor disorder (e.g., with the presence or absence of a tumor). Thepresence or quantity of such markers is independent of the disease.Therefore, these markers can serve to indicate whether a particularcourse of treatment is effective in lessening a disease state ordisorder. Surrogate markers are of particular use when the presence orextent of a disease state or disorder is difficult to assess throughstandard methodologies (e.g., early stage tumors), or when an assessmentof disease progression is desired before a potentially dangerousclinical endpoint is reached (e.g., an assessment of cardiovasculardisease can be made using cholesterol levels as a surrogate marker, andan analysis of HIV infection can be made using HIV RNA levels as asurrogate marker, well in advance of the undesirable clinical outcomesof myocardial infarction or fully-developed AIDS). Examples of the useof surrogate markers in the art include: Koomen et al. (2000) J. Mass.Spectrom. 35: 258-264; and James (1994) AIDS Treatment News Archive 209.

[0671] The 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577 molecules of the invention are also useful aspharmacodynamic markers As used herein, a “pharmacodynamic marker” is anobjective biochemical marker which correlates specifically with drugeffects. The presence or quantity of a pharmacodynamic marker is notrelated to the disease state or disorder for which the drug is beingadministered; therefore, the presence or quantity of the marker isindicative of the presence or activity of the drug in a subject. Forexample, a pharmacodynamic marker can be indicative of the concentrationof the drug in a biological tissue, in that the marker is eitherexpressed or transcribed or not expressed or transcribed in that tissuein relationship to the level of the drug. In this fashion, thedistribution or uptake of the drug can be monitored by thepharmacodynamic marker. Similarly, the presence or quantity of thepharmacodynamic marker can be related to the presence or quantity of themetabolic product of a drug, such that the presence or quantity of themarker is indicative of the relative breakdown rate of the drug in vivo.Pharmacodynamic markers are of particular use in increasing thesensitivity of detection of drug effects, particularly when the drug isadministered in low doses. Since even a small amount of a drug can besufficient to activate multiple rounds of marker (e.g., a 27877, 18080,14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 marker)transcription or expression, the amplified marker can be in a quantitywhich is more readily detectable than the drug itself. Also, the markercan be more easily detected due to the nature of the marker itself; forexample, using the methods described herein, anti-27877, 18080, 14081,32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 antibodies canbe employed in an immune-based detection system for a 27877, 18080,14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 proteinmarker, or 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577-specific radiolabeled probes can be used to detecta 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552or 65577 mRNA marker. Furthermore, the use of a pharmacodynamic markercan offer mechanism-based prediction of risk due to drug treatmentbeyond the range of possible direct observations. Examples of the use ofpharmacodynamic markers in the art include: Matsuda et al. U.S. Pat. No.6,033,862; Hattis et al. (1991) Env. Health Perspect. 90: 229-238;Schentag (1999) Am. J. Health-Syst. Pharm. 56 Suppl. 3: S21-S24; andNicolau (1999) Am. J. Health-Syst. Pharm. 56 Suppl. 3: S16-S20.

[0672] The 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577 molecules of the invention are also useful aspharmacogenomic markers. As used herein, a “pharmacogenomic marker” isan objective biochemical marker which correlates with a specificclinical drug response or susceptibility in a subject (see, e.g., McLeodet al. (1999) Eur. J. Cancer 35:1650-1652). The presence or quantity ofthe pharmacogenomic marker is related to the predicted response of thesubject to a specific drug or class of drugs prior to administration ofthe drug. By assessing the presence or quantity of one or morepharmacogenomic markers in a subject, a drug therapy which is mostappropriate for the subject, or which is predicted to have a greaterdegree of success, can be selected. For example, based on the presenceor quantity of RNA, or protein (e.g., 27877, 18080, 14081, 32140, 50352,16658, 14223, 16002, 50566, 65552 or 65577 protein or RNA) for specifictumor markers in a subject, a drug or course of treatment can beselected that is optimized for the treatment of the specific tumorlikely to be present in the subject. Similarly, the presence or absenceof a specific sequence mutation in 27877, 18080, 14081, 32140, 50352,16658, 14223, 16002, 50566, 65552 or 65577 DNA can correlate with a27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or65577 drug response. The use of pharmacogenomic markers thereforepermits the application of the most appropriate treatment for eachsubject without having to administer the therapy.

[0673] Pharmaceutical Compositions

[0674] The nucleic acid and polypeptides, fragments thereof, as well asanti-27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566,65552 or 65577 antibodies (also referred to herein as “activecompounds”) of the invention can be incorporated into pharmaceuticalcompositions. Such compositions typically include the nucleic acidmolecule, protein, or antibody and a pharmaceutically acceptablecarrier. As used herein the language “pharmaceutically acceptablecarrier” includes solvents, dispersion media, coatings, antibacterialand antifungal agents, isotonic and absorption delaying agents, and thelike, compatible with pharmaceutical administration. Supplementaryactive compounds can also be incorporated into the compositions.

[0675] A pharmaceutical composition is formulated to be compatible withits intended route of administration. Examples of routes ofadministration include parenteral, e.g., intravenous, intradermal,subcutaneous, oral (e.g., inhalation), transdermal (topical),transmucosal, and rectal administration. Solutions or suspensions usedfor parenteral, intradermal, or subcutaneous application can include thefollowing components: a sterile diluent such as water for injection,saline solution, fixed oils, polyethylene glycols, glycerine, propyleneglycol or other synthetic solvents; antibacterial agents such as benzylalcohol or methyl parabens; antioxidants such as ascorbic acid or sodiumbisulfite; chelating agents such as ethylenediaminetetraacetic acid;buffers such as acetates, citrates or phosphates and agents for theadjustment of tonicity such as sodium chloride or dextrose. pH can beadjusted with acids or bases, such as hydrochloric acid or sodiumhydroxide. The parenteral preparation can be enclosed in ampoules,disposable syringes or multiple dose vials made of glass or plastic.

[0676] Pharmaceutical compositions suitable for injectable use includesterile aqueous solutions (where water soluble) or dispersions andsterile powders for the extemporaneous preparation of sterile injectablesolutions or dispersion. For intravenous administration, suitablecarriers include physiological saline, bacteriostatic water, CremophorELTM (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In allcases, the composition must be sterile and should be fluid to the extentthat easy syringability exists. It should be stable under the conditionsof manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, polyol (for example, glycerol, propylene glycol, andliquid polyetheylene glycol, and the like), and suitable mixturesthereof. The proper fluidity can be maintained, for example, by the useof a coating such as lecithin, by the maintenance of the requiredparticle size in the case of dispersion and by the use of surfactants.Prevention of the action of microorganisms can be achieved by variousantibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In manycases, it will be preferable to include isotonic agents, for example,sugars, polyalcohols such as manitol, sorbitol, sodium chloride in thecomposition. Prolonged absorption of the injectable compositions can bebrought about by including in the composition an agent which delaysabsorption, for example, aluminum monostearate and gelatin.

[0677] Sterile injectable solutions can be prepared by incorporating theactive compound in the required amount in an appropriate solvent withone or a combination of ingredients enumerated above, as required,followed by filtered sterilization. Generally, dispersions are preparedby incorporating the active compound into a sterile vehicle whichcontains a basic dispersion medium and the required other ingredientsfrom those enumerated above. In the case of sterile powders for thepreparation of sterile injectable solutions, the preferred methods ofpreparation are vacuum drying and freeze-drying which yields a powder ofthe active ingredient plus any additional desired ingredient from apreviously sterile-filtered solution thereof.

[0678] Oral compositions generally include an inert diluent or an ediblecarrier. For the purpose of oral therapeutic administration, the activecompound can be incorporated with excipients and used in the form oftablets, troches, or capsules, e.g., gelatin capsules. Oral compositionscan also be prepared using a fluid carrier for use as a mouthwash.Pharmaceutically compatible binding agents, and/or adjuvant materialscan be included as part of the composition. The tablets, pills,capsules, troches and the like can contain any of the followingingredients, or compounds of a similar nature: a binder such asmicrocrystalline cellulose, gum tragacanth or gelatin; an excipient suchas starch or lactose, a disintegrating agent such as alginic acid,Primogel, or corn starch; a lubricant such as magnesium stearate orSterotes; a glidant such as colloidal silicon dioxide; a sweeteningagent such as sucrose or saccharin; or a flavoring agent such aspeppermint, methyl salicylate, or orange flavoring.

[0679] For administration by inhalation, the compounds are delivered inthe form of an aerosol spray from pressured container or dispenser whichcontains a suitable propellant, e.g., a gas such as carbon dioxide, or anebulizer.

[0680] Systemic administration can also be by transmucosal ortransdermal means. For transmucosal or transdermal administration,penetrants appropriate to the barrier to be permeated are used in theformulation. Such penetrants are generally known in the art, andinclude, for example, for transmucosal administration, detergents, bilesalts, and fusidic acid derivatives. Transmucosal administration can beaccomplished through the use of nasal sprays or suppositories. Fortransdermal administration, the active compounds are formulated intoointments, salves, gels, or creams as generally known in the art.

[0681] The compounds can also be prepared in the form of suppositories(e.g., with conventional suppository bases such as cocoa butter andother glycerides) or retention enemas for rectal delivery.

[0682] In one embodiment, the active compounds are prepared withcarriers that will protect the compound against rapid elimination fromthe body, such as a controlled release formulation, including implantsand microencapsulated delivery systems. Biodegradable, biocompatiblepolymers can be used, such as ethylene vinyl acetate, polyanhydrides,polyglycolic acid, collagen, polyorthoesters, and polylactic acid.Methods for preparation of such formulations will be apparent to thoseskilled in the art. The materials can also be obtained commercially fromAlza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions(including liposomes targeted to infected cells with monoclonalantibodies to viral antigens) can also be used as pharmaceuticallyacceptable carriers. These can be prepared according to methods known tothose skilled in the art, for example, as described in U.S. Pat. No.4,522,811.

[0683] It is advantageous to formulate oral or parenteral compositionsin dosage unit form for ease of administration and uniformity of dosage.Dosage unit form as used herein refers to physically discrete unitssuited as unitary dosages for the subject to be treated; each unitcontaining a predetermined quantity of active compound calculated toproduce the desired therapeutic effect in association with the requiredpharmaceutical carrier.

[0684] Toxicity and therapeutic efficacy of such compounds can bedetermined by standard pharmaceutical procedures in cell cultures orexperimental animals, e.g., for determining the LD₅₀ (the dose lethal to50% of the population) and the ED₅₀ (the dose therapeutically effectivein 50% of the population). The dose ratio between toxic and therapeuticeffects is the therapeutic index and it can be expressed as the ratioLD₅₀/ED₅₀. Compounds which exhibit high therapeutic indices arepreferred. While compounds that exhibit toxic side effects can be used,care should be taken to design a delivery system that targets suchcompounds to the site of affected tissue in order to minimize potentialdamage to uninfected cells and, thereby, reduce side effects.

[0685] The data obtained from the cell culture assays and animal studiescan be used in formulating a range of dosage for use in humans. Thedosage of such compounds lies preferably within a range of circulatingconcentrations that include the ED₅₀ with little or no toxicity. Thedosage can vary within this range depending upon the dosage formemployed and the route of administration utilized. For any compound usedin the method of the invention, the therapeutically effective dose canbe estimated initially from cell culture assays. A dose can beformulated in animal models to achieve a circulating plasmaconcentration range that includes the IC₅₀ (i.e., the concentration ofthe test compound which achieves a half-maximal inhibition of symptoms)as determined in cell culture. Such information can be used to moreaccurately determine useful doses in humans. Levels in plasma can bemeasured, for example, by high performance liquid chromatography.

[0686] As defined herein, a therapeutically effective amount of proteinor polypeptide (i.e., an effective dosage) ranges from about 0.001 to 30mg/kg body weight, preferably about 0.01 to 25 mg/kg body weight, morepreferably about 0.1 to 20 mg/kg body weight, and even more preferablyabout 1 to 10 mg/kg, 2 to 9 mg/kg, 3 to 8 mg/kg, 4 to 7 mg/kg, or 5 to 6mg/kg body weight. The protein or polypeptide can be administered onetime per week for between about 1 to 10 weeks, preferably between 2 to 8weeks, more preferably between about 3 to 7 weeks, and even morepreferably for about 4, 5, or 6 weeks. The skilled artisan willappreciate that certain factors can influence the dosage and timingrequired to effectively treat a subject, including but not limited tothe severity of the disease or disorder, previous treatments, thegeneral health and/or age of the subject, and other diseases present.Moreover, treatment of a subject with a therapeutically effective amountof a protein, polypeptide, or antibody, unconjugated or conjugated asdescribed herein, can include a single treatment or, preferably, caninclude a series of treatments.

[0687] For antibodies, the preferred dosage is 0.1 mg/kg of body weight(generally 10 mg/kg to 20 mg/kg). If the antibody is to act in thebrain, a dosage of 50 mg/kg to 100 mg/kg is usually appropriate.Generally, partially human antibodies and fully human antibodies have alonger half-life within the human body than other antibodies.Accordingly, lower dosages and less frequent administration is oftenpossible. Modifications such as lipidation can be used to stabilizeantibodies and to enhance uptake and tissue penetration (e.g., into thebrain). A method for lipidation of antibodies is described by Cruikshanket al. ((1997) J. Acquired Immune Deficiency Syndromes and HumanRetrovirology 14:193).

[0688] The present invention encompasses agents which modulateexpression or activity. An agent can, for example, be a small molecule.For example, such small molecules include, but are not limited to,peptides, peptidomimetics (e.g., peptoids), amino acids, amino acidanalogs, polynucleotides, polynucleotide analogs, nucleotides,nucleotide analogs, organic or inorganic compounds (i.e., includingheteroorganic and organometallic compounds) having a molecular weightless than about 10,000 grams per mole, organic or inorganic compoundshaving a molecular weight less than about 5,000 grams per mole, organicor inorganic compounds having a molecular weight less than about 1,000grams per mole, organic or inorganic compounds having a molecular weightless than about 500 grams per mole, and salts, esters, and otherpharmaceutically acceptable forms of such compounds.

[0689] Exemplary doses include milligram or microgram amounts of thesmall molecule per kilogram of subject or sample weight (e.g., about 1microgram per kilogram to about 500 milligrams per kilogram, about 100micrograms per kilogram to about 5 milligrams per kilogram, or about 1microgram per kilogram to about 50 micrograms per kilogram. It isfurthermore understood that appropriate doses of a small molecule dependupon the potency of the small molecule with respect to the expression oractivity to be modulated. When one or more of these small molecules isto be administered to an animal (e.g., a human) in order to modulateexpression or activity of a polypeptide or nucleic acid of theinvention, a physician, veterinarian, or researcher can, for example,prescribe a relatively low dose at first, subsequently increasing thedose until an appropriate response is obtained. In addition, it isunderstood that the specific dose level for any particular animalsubject will depend upon a variety of factors including the activity ofthe specific compound employed, the age, body weight, general health,gender, and diet of the subject, the time of administration, the routeof administration, the rate of excretion, any drug combination, and thedegree of expression or activity to be modulated.

[0690] The nucleic acid molecules of the invention can be inserted intovectors and used as gene therapy vectors. Gene therapy vectors can bedelivered to a subject by, for example, intravenous injection, localadministration (see U.S. Pat. No. 5,328,470) or by stereotacticinjection (see e.g., Chen et al. (1994) Proc. Natl. Acad. Sci. USA91:3054-3057). The pharmaceutical preparation of the gene therapy vectorcan include the gene therapy vector in an acceptable diluent, or cancomprise a slow release matrix in which the gene delivery vehicle isimbedded. Alternatively, where the complete gene delivery vector can beproduced intact from recombinant cells, e.g., retroviral vectors, thepharmaceutical preparation can include one or more cells which producethe gene delivery system.

[0691] The pharmaceutical compositions can be included in a container,pack, or dispenser together with instructions for administration.

[0692] Methods of Treatment:

[0693] The present invention provides for both prophylactic andtherapeutic methods of treating a subject at risk of (or susceptible to)a disorder or having a disorder associated with aberrant or unwanted27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or65577 expression or activity. As used herein, the term “treatment” isdefined as the application or administration of a therapeutic agent to apatient, or application or administration of a therapeutic agent to anisolated tissue or cell line from a patient, who has a disease, asymptom of disease or a predisposition toward a disease, with thepurpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate,improve or affect the disease, the symptoms of disease or thepredisposition toward disease. A therapeutic agent includes, but is notlimited to, small molecules, peptides, antibodies, ribozymes andantisense oligonucleotides.

[0694] With regards to both prophylactic and therapeutic methods oftreatment, such treatments can be specifically tailored or modified,based on knowledge obtained from the field of pharmacogenomics.“Pharmacogenomics”, as used herein, refers to the application ofgenomics technologies such as gene sequencing, statistical genetics, andgene expression analysis to drugs in clinical development and on themarket. More specifically, the term refers the study of how a patient'sgenes determine his or her response to a drug (e.g., a patient's “drugresponse phenotype”, or “drug response genotype”.) Thus, another aspectof the invention provides methods for tailoring an individual'sprophylactic or therapeutic treatment with either the 27877, 18080,14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577molecules of the present invention or 27877, 18080, 14081, 32140, 50352,16658, 14223, 16002, 50566, 65552 or 65577 modulators according to thatindividual's drug response genotype. Pharmacogenomics allows a clinicianor physician to target prophylactic or therapeutic treatments topatients who will most benefit from the treatment and to avoid treatmentof patients who will experience toxic drug-related side effects.

[0695] In one aspect, the invention provides a method for preventing ina subject, a disease or condition associated with an aberrant orunwanted 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566,65552 or 65577 expression or activity, by administering to the subject a27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or65577 or an agent which modulates 27877, 18080, 14081, 32140, 50352,16658, 14223, 16002, 50566, 65552 or 65577 expression or at least one27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or65577 activity. Subjects at risk for a disease which is caused orcontributed to by aberrant or unwanted 27877, 18080, 14081, 32140,50352, 16658, 14223, 16002, 50566, 65552 or 65577 expression or activitycan be identified by, for example, any or a combination of diagnostic orprognostic assays as described herein. Administration of a prophylacticagent can occur prior to the manifestation of symptoms characteristic ofthe 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552or 65577 aberrance, such that a disease or disorder is prevented or,alternatively, delayed in its progression. Depending on the type of27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or65577 aberrance, for example, a 27877, 18080, 14081, 32140, 50352,16658, 14223, 16002, 50566, 65552 or 65577, 27877, 18080, 14081, 32140,50352, 16658, 14223, 16002, 50566, 65552 or 65577 agonist or 27877,18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577antagonist agent can be used for treating the subject. The appropriateagent can be determined based on screening assays described herein.

[0696] It is possible that some 27877, 18080, 14081, 32140, 50352,16658, 14223, 16002, 50566, 65552 or 65577 disorders can be caused, atleast in part, by an abnormal level of gene product, or by the presenceof a gene product exhibiting abnormal activity. As such, the reductionin the level and/or activity of such gene products would bring about theamelioration of disorder symptoms.

[0697] The 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577 molecules can act as novel diagnostic targets andtherapeutic agents for controlling one or more of a cellularproliferative and/or differentiative disorder, brain, blood vessel,platelet, breast, colon, kidney, lung, ovarian, prostate, hematopoeitic,pancreatic, skeletal muscle, testicular, skin, hormonal, associated withbone metabolism, immune e.g., inflammatory, cardiovascular, endothelialcell, liver, viral diseases, pain, metabolic, anemias, angiogenesis,neoplastic, endocrine, neurological or heart disorder, all of which aredescribed above.

[0698] As discussed, successful treatment of 27877, 18080, 14081, 32140,50352, 16658, 14223, 16002, 50566, 65552 or 65577 disorders can bebrought about by techniques that serve to inhibit the expression oractivity of target gene products. For example, compounds, e.g., an agentidentified using an assays described above, that proves to exhibitnegative modulatory activity, can be used in accordance with theinvention to prevent and/or ameliorate symptoms of 27877, 18080, 14081,32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 disorders. Suchmolecules can include, but are not limited to peptides, phosphopeptides,small organic or inorganic molecules, or antibodies (including, forexample, polyclonal, monoclonal, humanized, human, anti-idiotypic,chimeric or single chain antibodies, and Fab, F(ab′)₂ and Fab expressionlibrary fragments, scFV molecules, and epitope-binding fragmentsthereof).

[0699] Further, antisense and ribozyme molecules that inhibit expressionof the target gene can also be used in accordance with the invention toreduce the level of target gene expression, thus effectively reducingthe level of target gene activity. Still further, triple helix moleculescan be utilized in reducing the level of target gene activity.Antisense, ribozyme and triple helix molecules are discussed above.

[0700] It is possible that the use of antisense, ribozyme, and/or triplehelix molecules to reduce or inhibit mutant gene expression can alsoreduce or inhibit the transcription (triple helix) and/or translation(antisense, ribozyme) of mRNA produced by normal target gene alleles,such that the concentration of normal target gene product present can belower than is necessary for a normal phenotype. In such cases, nucleicacid molecules that encode and express target gene polypeptidesexhibiting normal target gene activity can be introduced into cells viagene therapy method. Alternatively, in instances in that the target geneencodes an extracellular protein, it can be preferable to co-administernormal target gene protein into the cell or tissue in order to maintainthe requisite level of cellular or tissue target gene activity.

[0701] Another method by which nucleic acid molecules can be utilized intreating or preventing a disease characterized by 27877, 18080, 14081,32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 expression isthrough the use of aptamer molecules specific for 27877, 18080, 14081,32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 protein.Aptamers are nucleic acid molecules having a tertiary structure whichpermits them to specifically or selectively bind to protein ligands(see, e.g., Osborne et al. (1997) Curr. Opin. Chem Biol. 1: 5-9; andPatel (1997) Curr Opin Chem Biol 1:32-46). Since nucleic acid moleculescan in many cases be more conveniently introduced into target cells thantherapeutic protein molecules can be, aptamers offer a method by which27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or65577 protein activity can be specifically decreased without theintroduction of drugs or other molecules which can have pluripotenteffects.

[0702] Antibodies can be generated that are both specific for targetgene product and that reduce target gene product activity. Suchantibodies can, therefore, by administered in instances whereby negativemodulatory techniques are appropriate for the treatment of 27877, 18080,14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577disorders. For a description of antibodies, see the Antibody sectionabove.

[0703] In circumstances wherein injection of an animal or a humansubject with a 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577 protein or epitope for stimulating antibodyproduction is harmful to the subject, it is possible to generate animmune response against 27877, 18080, 14081, 32140, 50352, 16658, 14223,16002, 50566, 65552 or 65577 through the use of anti-idiotypicantibodies (see, for example, Herlyn (1999) Ann Med 31:66-78; andBhattacharya-Chatterjee and Foon (1998) Cancer Treat Res. 94:51-68). Ifan anti-idiotypic antibody is introduced into a mammal or human subject,it should stimulate the production of anti-anti-idiotypic antibodies,which should be specific to the 27877, 18080, 14081, 32140, 50352,16658, 14223, 16002, 50566, 65552 or 65577 protein.

[0704] Vaccines directed to a disease characterized by 27877, 18080,14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577expression can also be generated in this fashion.

[0705] In instances where the target antigen is intracellular and wholeantibodies are used, internalizing antibodies can be preferred.Lipofectin or liposomes can be used to deliver the antibody or afragment of the Fab region that binds to the target antigen into cells.Where fragments of the antibody are used, the smallest inhibitoryfragment that binds to the target antigen is preferred. For example,peptides having an amino acid sequence corresponding to the Fv region ofthe antibody can be used. Alternatively, single chain neutralizingantibodies that bind to intracellular target antigens can also beadministered. Such single chain antibodies can be administered, forexample, by expressing nucleotide sequences encoding single-chainantibodies within the target cell population (see e.g., Marasco et al.(1993) Proc. Natl. Acad. Sci. USA 90:7889-7893).

[0706] The identified compounds that inhibit target gene expression,synthesis and/or activity can be administered to a patient attherapeutically effective doses to prevent, treat or ameliorate 27877,18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577disorders. A therapeutically effective dose refers to that amount of thecompound sufficient to result in amelioration of symptoms of thedisorders. Toxicity and therapeutic efficacy of such compounds can bedetermined by standard pharmaceutical procedures as described above.

[0707] The data obtained from the cell culture assays and animal studiescan be used in formulating a range of dosage for use in humans. Thedosage of such compounds lies preferably within a range of circulatingconcentrations that include the ED₅₀ with little or no toxicity. Thedosage can vary within this range depending upon the dosage formemployed and the route of administration utilized. For any compound usedin the method of the invention, the therapeutically effective dose canbe estimated initially from cell culture assays. A dose can beformulated in animal models to achieve a circulating plasmaconcentration range that includes the IC₅₀ (i.e., the concentration ofthe test compound that achieves a half-maximal inhibition of symptoms)as determined in cell culture. Such information can be used to moreaccurately determine useful doses in humans. Levels in plasma can bemeasured, for example, by high performance liquid chromatography.

[0708] Another example of determination of effective dose for anindividual is the ability to directly assay levels of “free” and “bound”compound in the serum of the test subject. Such assays can utilizeantibody mimics and/or “biosensors” that have been created throughmolecular imprinting techniques. The compound which is able to modulate27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or65577 activity is used as a template, or “imprinting molecule”, tospatially organize polymerizable monomers prior to their polymerizationwith catalytic reagents. The subsequent removal of the imprintedmolecule leaves a polymer matrix which contains a repeated “negativeimage” of the compound and is able to selectively rebind the moleculeunder biological assay conditions. A detailed review of this techniquecan be seen in Ansell et al (1996) Current Opinion in Biotechnology7:89-94 and in Shea (1994) Trends in Polymer Science 2:166-173. Such“imprinted” affinity matrixes are amenable to ligand-binding assays,whereby the immobilized monoclonal antibody component is replaced by anappropriately imprinted matrix. An example of the use of such matrixesin this way can be seen in Vlatakis et al (1993) Nature 361:645-647.Through the use of isotope-labeling, the “free” concentration ofcompound which modulates the expression or activity of 27877, 18080,14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 can bereadily monitored and used in calculations of IC₅₀.

[0709] Such “imprinted” affinity matrixes can also be designed toinclude fluorescent groups whose photon-emitting properties measurablychange upon local and selective binding of target compound. Thesechanges can be readily assayed in real time using appropriate fiberopticdevices, in turn allowing the dose in a test subject to be quicklyoptimized based on its individual IC₅₀. An rudimentary example of such a“biosensor” is discussed in Kriz et al (1995) Analytical Chemistry67:2142-2144.

[0710] Another aspect of the invention pertains to methods of modulating27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or65577 expression or activity for therapeutic purposes. Accordingly, inan exemplary embodiment, the modulatory method of the invention involvescontacting a cell with a 27877, 18080, 14081, 32140, 50352, 16658,14223, 16002, 50566, 65552 or 65577 or agent that modulates one or moreof the activities of 27877, 18080, 14081, 32140, 50352, 16658, 14223,16002, 50566, 65552 or 65577 protein activity associated with the cell.An agent that modulates 27877, 18080, 14081, 32140, 50352, 16658, 14223,16002, 50566, 65552 or 65577 protein activity can be an agent asdescribed herein, such as a nucleic acid or a protein, anaturally-occurring target molecule of a 27877, 18080, 14081, 32140,50352, 16658, 14223, 16002, 50566, 65552 or 65577 protein (e.g., a27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or65577 substrate or receptor), a 27877, 18080, 14081, 32140, 50352,16658, 14223, 16002, 50566, 65552 or 65577 antibody, a 27877, 18080,14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 agonistor antagonist, a peptidomimetic of a 27877, 18080, 14081, 32140, 50352,16658, 14223, 16002, 50566, 65552 or 65577 agonist or antagonist, orother small molecule.

[0711] In one embodiment, the agent stimulates one or 27877, 18080,14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577activities. Examples of such stimulatory agents include active 27877,18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577protein and a nucleic acid molecule encoding 27877, 18080, 14081, 32140,50352, 16658, 14223, 16002, 50566, 65552 or 65577. In anotherembodiment, the agent inhibits one or more 27877, 18080, 14081, 32140,50352, 16658, 14223, 16002, 50566, 65552 or 65577 activities. Examplesof such inhibitory agents include antisense 27877, 18080, 14081, 32140,50352, 16658, 14223, 16002, 50566, 65552 or 65577 nucleic acidmolecules, anti-27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577 antibodies, and 27877, 18080, 14081, 32140, 50352,16658, 14223, 16002, 50566, 65552 or 65577 inhibitors. These modulatorymethods can be performed in vitro (e.g., by culturing the cell with theagent) or, alternatively, in vivo (e.g., by administering the agent to asubject). As such, the present invention provides methods of treating anindividual afflicted with a disease or disorder characterized byaberrant or unwanted expression or activity of a 27877, 18080, 14081,32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 protein ornucleic acid molecule. In one embodiment, the method involvesadministering an agent (e.g., an agent identified by a screening assaydescribed herein), or combination of agents that modulates (e.g., upregulates or down regulates) 27877, 18080, 14081, 32140, 50352, 16658,14223, 16002, 50566, 65552 or 65577 expression or activity. In anotherembodiment, the method involves administering a 27877, 18080, 14081,32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 protein ornucleic acid molecule as therapy to compensate for reduced, aberrant, orunwanted 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566,65552 or 65577 expression or activity.

[0712] Stimulation of 27877, 18080, 14081, 32140, 50352, 16658, 14223,16002, 50566, 65552 or 65577 activity is desirable in situations inwhich 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566,65552 or 65577 is abnormally downregulated and/or in which increased27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or65577 activity is likely to have a beneficial effect. For example,stimulation of 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577 activity is desirable in situations in which a27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or65577 is downregulated and/or in which increased 27877, 18080, 14081,32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 activity islikely to have a beneficial effect. Likewise, inhibition of 27877,18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577activity is desirable in situations in which 27877, 18080, 14081, 32140,50352, 16658, 14223, 16002, 50566, 65552 or 65577 is abnormallyupregulated and/or in which decreased 27877, 18080, 14081, 32140, 50352,16658, 14223, 16002, 50566, 65552 or 65577 activity is likely to have abeneficial effect.

[0713] Pharmacogenomics

[0714] The 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577 molecules of the present invention, as well asagents, or modulators which have a stimulatory or inhibitory effect on27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or65577 activity (e.g., 27877, 18080, 14081, 32140, 50352, 16658, 14223,16002, 50566, 65552 or 65577 gene expression) as identified by ascreening assay described herein can be administered to individuals totreat (prophylactically or therapeutically) 27877, 18080, 14081, 32140,50352, 16658, 14223, 16002, 50566, 65552 or 65577-associated disorders(e.g., aberrant or deficient phospholipase activity, serinecarboxypeptidase activity, trypsin-like serine protease activity,aldehyde dehydrogenase activity, ubiquitin-protein ligase activity,protein kinase activity, hydrolase activity or matrix metalloproteinaseactivity.) associated with aberrant or unwanted 27877, 18080, 14081,32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 activity.

[0715] In conjunction with such treatment, pharmacogenomics (i.e., thestudy of the relationship between an individual's genotype and thatindividual's response to a foreign compound or drug) can be considered.Differences in metabolism of therapeutics can lead to severe toxicity ortherapeutic failure by altering the relation between dose and bloodconcentration of the pharmacologically active drug. Thus, a physician orclinician can consider applying knowledge obtained in relevantpharmacogenomics studies in determining whether to administer a 27877,18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577molecule or 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577 modulator as well as tailoring the dosage and/ortherapeutic regimen of treatment with a 27877, 18080, 14081, 32140,50352, 16658, 14223, 16002, 50566, 65552 or 65577 molecule or 27877,18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577modulator.

[0716] Pharmacogenomics deals with clinically significant hereditaryvariations in the response to drugs due to altered drug disposition andabnormal action in affected persons. See, for example, Eichelbaum et al.(1996) Clin. Exp. Pharmacol. Physiol. 23:983-985 and Linder et al.(1997) Clin. Chem. 43:254-266. In general, two types of pharmacogeneticconditions can be differentiated. Genetic conditions transmitted as asingle factor altering the way drugs act on the body (altered drugaction) or genetic conditions transmitted as single factors altering theway the body acts on drugs (altered drug metabolism). Thesepharmacogenetic conditions can occur either as rare genetic defects oras naturally-occurring polymorphisms. For example, glucose-6-phosphatedehydrogenase deficiency (G6PD) is a common inherited enzymopathy inwhich the main clinical complication is haemolysis after ingestion ofoxidant drugs (anti-malarials, sulfonamides, analgesics, nitrofurans)and consumption of fava beans.

[0717] One pharmacogenomics approach to identifying genes that predictdrug response, known as “a genome-wide association”, relies primarily ona high-resolution map of the human genome consisting of already knowngene-related markers (e.g., a “bi-allelic” gene marker map whichconsists of 60,000-100,000 polymorphic or variable sites on the humangenome, each of which has two variants.) Such a high-resolution geneticmap can be compared to a map of the genome of each of a statisticallysignificant number of patients taking part in a Phase II/III drug trialto identify markers associated with a particular observed drug responseor side effect. Alternatively, such a high resolution map can begenerated from a combination of some ten-million known single nucleotidepolymorphisms (SNPs) in the human genome. As used herein, a “SNP” is acommon alteration that occurs in a single nucleotide base in a stretchof DNA. For example, a SNP can occur once per every 1000 bases of DNA. ASNP can be involved in a disease process, however, the vast majority cannot be disease-associated. Given a genetic map based on the occurrenceof such SNPs, individuals can be grouped into genetic categoriesdepending on a particular pattern of SNPs in their individual genome. Insuch a manner, treatment regimens can be tailored to groups ofgenetically similar individuals, taking into account traits that can becommon among such genetically similar individuals.

[0718] Alternatively, a method termed the “candidate gene approach”, canbe utilized to identify genes that predict drug response. According tothis method, if a gene that encodes a drug's target is known (e.g., a27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or65577 protein of the present invention), all common variants of thatgene can be fairly easily identified in the population and it can bedetermined if having one version of the gene versus another isassociated with a particular drug response.

[0719] Alternatively, a method termed the “gene expression profiling”,can be utilized to identify genes that predict drug response. Forexample, the gene expression of an animal dosed with a drug (e.g., a27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or65577 molecule or 27877, 18080, 14081, 32140, 50352, 16658, 14223,16002, 50566, 65552 or 65577 modulator of the present invention) cangive an indication whether gene pathways related to toxicity have beenturned on.

[0720] Information generated from more than one of the abovepharmacogenomics approaches can be used to determine appropriate dosageand treatment regimens for prophylactic or therapeutic treatment of anindividual. This knowledge, when applied to dosing or drug selection,can avoid adverse reactions or therapeutic failure and thus enhancetherapeutic or prophylactic efficiency when treating a subject with a27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or65577 molecule or 27877, 18080, 14081, 32140, 50352, 16658, 14223,16002, 50566, 65552 or 65577 modulator, such as a modulator identifiedby one of the exemplary screening assays described herein.

[0721] The present invention further provides methods for identifyingnew agents, or combinations, that are based on identifying agents thatmodulate the activity of one or more of the gene products encoded by oneor more of the 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577 genes of the present invention, wherein theseproducts can be associated with resistance of the cells to a therapeuticagent. Specifically, the activity of the proteins encoded by the 27877,18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577genes of the present invention can be used as a basis for identifyingagents for overcoming agent resistance. By blocking the activity of oneor more of the resistance proteins, target cells, e.g., human cells,will become sensitive to treatment with an agent to which the unmodifiedtarget cells were resistant.

[0722] Monitoring the influence of agents (e.g., drugs) on theexpression or activity of a 27877, 18080, 14081, 32140, 50352, 16658,14223, 16002, 50566, 65552 or 65577 protein can be applied in clinicaltrials. For example, the effectiveness of an agent determined by ascreening assay as described herein to increase 27877, 18080, 14081,32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 geneexpression, protein levels, or upregulate 27877, 18080, 14081, 32140,50352, 16658, 14223, 16002, 50566, 65552 or 65577 activity, can bemonitored in clinical trials of subjects exhibiting decreased 27877,18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577gene expression, protein levels, or downregulated 27877, 18080, 14081,32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 activity.Alternatively, the effectiveness of an agent determined by a screeningassay to decrease 27877, 18080, 14081, 32140, 50352, 16658, 14223,16002, 50566, 65552 or 65577 gene expression, protein levels, ordownregulate 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577 activity, can be monitored in clinical trials ofsubjects exhibiting increased 27877, 18080, 14081, 32140, 50352, 16658,14223, 16002, 50566, 65552 or 65577 gene expression, protein levels, orupregulated 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577 activity. In such clinical trials, the expressionor activity of a 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577 gene, and preferably, other genes that have beenimplicated in, for example, a protein kinase-associated or another27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or65577-associated disorder can be used as a “read out” or markers of thephenotype of a particular cell.

[0723] Other Embodiments

[0724] In another aspect, the invention features a method of analyzing aplurality of capture probes. The method is useful, e.g., to analyze geneexpression. The method includes: providing a two dimensional arrayhaving a plurality of addresses, each address of the plurality beingpositionally distinguishable from each other address of the plurality,and each address of the plurality having a unique capture probe, e.g., anucleic acid or peptide sequence, wherein the capture probes are from acell or subject which expresses 27877, 18080, 14081, 32140, 50352,16658, 14223, 16002, 50566, 65552 or 65577 or from a cell or subject inwhich a 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566,65552 or 65577 mediated response has been elicited; contacting the arraywith a 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566,65552 or 65577 nucleic acid (preferably purified), a 27877, 18080,14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577polypeptide (preferably purified), or an anti-27877, 18080, 14081,32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 antibody, andthereby evaluating the plurality of capture probes. Binding, e.g., inthe case of a nucleic acid, hybridization with a capture probe at anaddress of the plurality, is detected, e.g., by a signal generated froma label attached to the 27877, 18080, 14081, 32140, 50352, 16658, 14223,16002, 50566, 65552 or 65577 nucleic acid, polypeptide, or antibody.

[0725] The capture probes can be a set of nucleic acids from a selectedsample, e.g., a sample of nucleic acids derived from a control ornon-stimulated tissue or cell.

[0726] The method can include contacting the 27877, 18080, 14081, 32140,50352, 16658, 14223, 16002, 50566, 65552 or 65577 nucleic acid,polypeptide, or antibody with a first array having a plurality ofcapture probes and a second array having a different plurality ofcapture probes. The results of each hybridization can be compared, e.g.,to analyze differences in expression between a first and second sample.The first plurality of capture probes can be from a control sample,e.g., a wild type, normal, or non-diseased, non-stimulated, sample,e.g., a biological fluid, tissue, or cell sample. The second pluralityof capture probes can be from an experimental sample, e.g., a mutanttype, at risk, disease-state or disorder-state, or stimulated, sample,e.g., a biological fluid, tissue, or cell sample.

[0727] The plurality of capture probes can be a plurality of nucleicacid probes each of which specifically hybridizes, with an allele of27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or65577. Such methods can be used to diagnose a subject, e.g., to evaluaterisk for a disease or disorder, to evaluate suitability of a selectedtreatment for a subject, to evaluate whether a subject has a disease ordisorder.

[0728] The method can be used to detect SNPs, as described above.

[0729] In another aspect, the invention features, a method of analyzing27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or65577, e.g., analyzing structure, function, or relatedness to othernucleic acid or amino acid sequences. The method includes: providing a27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or65577 nucleic acid or amino acid sequence; comparing the 27877, 18080,14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 sequencewith one or more preferably a plurality of sequences from a collectionof sequences, e.g., a nucleic acid or protein sequence database; tothereby analyze 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577.

[0730] The method can include evaluating the sequence identity between a27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or65577 sequence and a database sequence. The method can be performed byaccessing the database at a second site, e.g., over the internet.Preferred databases include GenBank™ and SwissProt.

[0731] In another aspect, the invention features, a set ofoligonucleotides, useful, e.g., for identifying SNP's, or identifyingspecific alleles of 27877, 18080, 14081, 32140, 50352, 16658, 14223,16002, 50566, 65552 or 65577. The set includes a plurality ofoligonucleotides, each of which has a different nucleotide at aninterrogation position, e.g., an SNP or the site of a mutation. In apreferred embodiment, the oligonucleotides of the plurality identical insequence with one another (except for differences in length). Theoligonucleotides can be provided with differential labels, such that anoligonucleotide which hybridizes to one allele provides a signal that isdistinguishable from an oligonucleotides which hybridizes to a secondallele.

[0732] The sequences of 27877, 18080, 14081, 32140, 50352, 16658, 14223,16002, 50566, 65552 or 65577 molecules are provided in a variety ofmediums to facilitate use thereof. A sequence can be provided as amanufacture, other than an isolated nucleic acid or amino acid molecule,which contains a 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577 molecule. Such a manufacture can provide anucleotide or amino acid sequence, e.g., an open reading frame, in aform which allows examination of the manufacture using means notdirectly applicable to examining the nucleotide or amino acid sequences,or a subset thereof, as they exist in nature or in purified form.

[0733] A 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566,65552 or 65577 nucleotide or amino acid sequence can be recorded oncomputer readable media. As used herein, “computer readable media”refers to any medium that can be read and accessed directly by acomputer. Such media include, but are not limited to: magnetic storagemedia, such as floppy discs, hard disc storage medium, and magnetictape; optical storage media such as compact disc and CD-ROM; electricalstorage media such as RAM, ROM, EPROM, EEPROM, and the like; and generalhard disks and hybrids of these categories such as magnetic/opticalstorage media. The medium is adapted or configured for having thereon27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or65577 sequence information of the present invention.

[0734] As used herein, the term “electronic apparatus” is intended toinclude any suitable computing or processing apparatus of other deviceconfigured or adapted for storing data or information. Examples ofelectronic apparatus suitable for use with the present invention includestand-alone computing apparatus; networks, including a local areanetwork (LAN), a wide area network (WAN) Internet, Intranet, andExtranet; electronic appliances such as personal digital assistants(PDAs), cellular phones, pagers, and the like; and local and distributedprocessing systems.

[0735] As used herein, “recorded” refers to a process for storing orencoding information on the electronic apparatus readable medium. Thoseskilled in the art can readily adopt any of the presently known methodsfor recording information on known media to generate manufacturescomprising the 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577 sequence information.

[0736] A variety of data storage structures are available to a skilledartisan for creating a computer readable medium having recorded thereona 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552or 65577 nucleotide or amino acid sequence of the present invention. Thechoice of the data storage structure will generally be based on themeans chosen to access the stored information. In addition, a variety ofdata processor programs and formats can be used to store the nucleotidesequence information of the present invention on computer readablemedium. The sequence information can be represented in a word processingtext file, formatted in commercially-available software such asWordPerfect and Microsoft Word, or represented in the form of an ASCIIfile, stored in a database application, such as DB2, Sybase, Oracle, orthe like. The skilled artisan can readily adapt any number of dataprocessor structuring formats (e.g., text file or database) in order toobtain computer readable medium having recorded thereon the nucleotidesequence information of the present invention.

[0737] By providing the 27877, 18080, 14081, 32140, 50352, 16658, 14223,16002, 50566, 65552 or 65577 nucleotide or amino acid sequences of theinvention in computer readable form, the skilled artisan can routinelyaccess the sequence information for a variety of purposes. For example,one skilled in the art can use the nucleotide or amino acid sequences ofthe invention in computer readable form to compare a target sequence ortarget structural motif with the sequence information stored within thedata storage means. A search is used to identify fragments or regions ofthe sequences of the invention which match a particular target sequenceor target motif.

[0738] The present invention therefore provides a medium for holdinginstructions for performing a method for determining whether a subjecthas a phospholipase, serine carboxypeptidase, trypsin-like serineprotease, aldehyde dehydrogenase, ubiquitin-protein ligase, proteinkinase, hydrolase or matrix metalloproteinase-associated or another27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or65577-associated disease or disorder or a pre-disposition to aphospholipase, serine carboxypeptidase, trypsin-like serine protease,aldehyde dehydrogenase, ubiquitin-protein ligase, protein kinase,hydrolase or matrix metalloproteinase-associated or another 27877,18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or65577-associated disease or disorder, wherein the method comprises thesteps of determining 27877, 18080, 14081, 32140, 50352, 16658, 14223,16002, 50566, 65552 or 65577 sequence information associated with thesubject and based on the 27877, 18080, 14081, 32140, 50352, 16658,14223, 16002, 50566, 65552 or 65577 sequence information, determiningwhether the subject has a phospholipase, serine carboxypeptidase,trypsin-like serine protease, aldehyde dehydrogenase, ubiquitin-proteinligase, protein kinase, hydrolase or matrix metalloproteinase-associatedor another 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577-associated disease or disorder and/or recommendinga particular treatment for the disease, disorder, or pre-diseasecondition.

[0739] The present invention further provides in an electronic systemand/or in a network, a method for determining whether a subject has aphospholipase, serine carboxypeptidase, trypsin-like serine protease,aldehyde dehydrogenase, ubiquitin-protein ligase, protein kinase,hydrolase or matrix metalloproteinase-associated or another 27877,18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or65577-associated disease or disorder or a pre-disposition to a diseaseassociated with 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577, wherein the method comprises the steps ofdetermining 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577 sequence information associated with the subject,and based on the 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577 sequence information, determining whether thesubject has a phospholipase, serine carboxypeptidase, trypsin-likeserine protease, aldehyde dehydrogenase, ubiquitin-protein ligase,protein kinase, hydrolase or matrix metalloproteinase-associated oranother 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566,65552 or 65577-associated disease or disorder or a pre-disposition to aphospholipase, serine carboxypeptidase, trypsin-like serine protease,aldehyde dehydrogenase, ubiquitin-protein ligase, protein kinase,hydrolase or matrix metalloproteinase-associated or another 27877,18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or65577-associated disease or disorder, and/or recommending a particulartreatment for the disease, disorder, or pre-disease condition. Themethod may further comprise the step of receiving phenotypic informationassociated with the subject and/or acquiring from a network phenotypicinformation associated with the subject.

[0740] The present invention also provides in a network, a method fordetermining whether a subject has a phospholipase, serinecarboxypeptidase, trypsin-like serine protease, aldehyde dehydrogenase,ubiquitin-protein ligase, protein kinase, hydrolase or matrixmetalloproteinase-associated or another 27877, 18080, 14081, 32140,50352, 16658, 14223, 16002, 50566, 65552 or 65577-associated disease ordisorder or a pre-disposition to a phospholipase, serinecarboxypeptidase, trypsin-like serine protease, aldehyde dehydrogenase,ubiquitin-protein ligase, protein kinase, hydrolase or matrixmetalloproteinase-associated or another 27877, 18080, 14081, 32140,50352, 16658, 14223, 16002, 50566, 65552 or 65577-associated disease ordisorder, said method comprising the steps of receiving 27877, 18080,14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 sequenceinformation from the subject and/or information related thereto,receiving phenotypic information associated with the subject, acquiringinformation from the network corresponding to 27877, 18080, 14081,32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 and/orcorresponding to a phospholipase, serine carboxypeptidase, trypsin-likeserine protease, aldehyde dehydrogenase, ubiquitin-protein ligase,protein kinase, hydrolase or matrix metalloproteinase-associated oranother 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566,65552 or 65577-associated disease or disorder, and based on one or moreof the phenotypic information, the 27877, 18080, 14081, 32140, 50352,16658, 14223, 16002, 50566, 65552 or 65577 information (e.g., sequenceinformation and/or information related thereto), and the acquiredinformation, determining whether the subject has a phospholipase, serinecarboxypeptidase, trypsin-like serine protease, aldehyde dehydrogenase,ubiquitin-protein ligase, protein kinase, hydrolase or matrixmetalloproteinase-associated or another 27877, 18080, 14081, 32140,50352, 16658, 14223, 16002, 50566, 65552 or 65577-associated disease ordisorder or a pre-disposition to a phospholipase, serinecarboxypeptidase, trypsin-like serine protease, aldehyde dehydrogenase,ubiquitin-protein ligase, protein kinase, hydrolase or matrixmetalloproteinase-associated or another 27877, 18080, 14081, 32140,50352, 16658, 14223, 16002, 50566, 65552 or 65577-associated disease ordisorder. The method may further comprise the step of recommending aparticular treatment for the disease, disorder, or pre-diseasecondition.

[0741] The present invention also provides a business method fordetermining whether a subject has a phospholipase, serinecarboxypeptidase, trypsin-like serine protease, aldehyde dehydrogenase,ubiquitin-protein ligase, protein kinase, hydrolase or matrixmetalloproteinase-associated or another 27877, 18080, 14081, 32140,50352, 16658, 14223, 16002, 50566, 65552 or 65577-associated disease ordisorder or a pre-disposition to a phospholipase, serinecarboxypeptidase, trypsin-like serine protease, aldehyde dehydrogenase,ubiquitin-protein ligase, protein kinase, hydrolase or matrixmetalloproteinase-associated or another 27877, 18080, 14081, 32140,50352, 16658, 14223, 16002, 50566, 65552 or 65577-associated disease ordisorder, said method comprising the steps of receiving informationrelated to 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577 (e.g., sequence information and/or informationrelated thereto), receiving phenotypic information associated with thesubject, acquiring information from the network related to 27877, 18080,14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 and/orrelated to a phospholipase, serine carboxypeptidase, trypsin-like serineprotease, aldehyde dehydrogenase, ubiquitin-protein ligase, proteinkinase, hydrolase or matrix metalloproteinase-associated or another27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or65577-associated disease or disorder, and based on one or more of thephenotypic information, the 27877, 18080, 14081, 32140, 50352, 16658,14223, 16002, 50566, 65552 or 65577 information, and the acquiredinformation, determining whether the subject has a phospholipase, serinecarboxypeptidase, trypsin-like serine protease, aldehyde dehydrogenase,ubiquitin-protein ligase, protein kinase, hydrolase or matrixmetalloproteinase-associated or another 27877, 18080, 14081, 32140,50352, 16658, 14223, 16002, 50566, 65552 or 65577-associated disease ordisorder or a pre-disposition to a phospholipase, serinecarboxypeptidase, trypsin-like serine protease, aldehyde dehydrogenase,ubiquitin-protein ligase, protein kinase, hydrolase or matrixmetalloproteinase-associated or another 27877, 18080, 14081, 32140,50352, 16658, 14223, 16002, 50566, 65552 or 65577-associated disease ordisorder. The method may further comprise the step of recommending aparticular treatment for the disease, disorder, or pre-diseasecondition.

[0742] The invention also includes an array comprising a 27877, 18080,14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 sequenceof the present invention. The array can be used to assay expression ofone or more genes in the array. In one embodiment, the array can be usedto assay gene expression in a tissue to ascertain tissue specificity ofgenes in the array. In this manner, up to about 7600 genes can besimultaneously assayed for expression, one of which can be 27877, 18080,14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577. Thisallows a profile to be developed showing a battery of genes specificallyexpressed in one or more tissues.

[0743] In addition to such qualitative information, the invention allowsthe quantitation of gene expression. Thus, not only tissue specificity,but also the level of expression of a battery of genes in the tissue ifascertainable. Thus, genes can be grouped on the basis of their tissueexpression per se and level of expression in that tissue. This isuseful, for example, in ascertaining the relationship of gene expressionin that tissue. Thus, one tissue can be perturbed and the effect on geneexpression in a second tissue can be determined. In this context, theeffect of one cell type on another cell type in response to a biologicalstimulus can be determined. In this context, the effect of one cell typeon another cell type in response to a biological stimulus can bedetermined. Such a determination is useful, for example, to know theeffect of cell-cell interaction at the level of gene expression. If anagent is administered therapeutically to treat one cell type but has anundesirable effect on another cell type, the invention provides an assayto determine the molecular basis of the undesirable effect and thusprovides the opportunity to co-administer a counteracting agent orotherwise treat the undesired effect. Similarly, even within a singlecell type, undesirable biological effects can be determined at themolecular level. Thus, the effects of an agent on expression of otherthan the target gene can be ascertained and counteracted.

[0744] In another embodiment, the array can be used to monitor the timecourse of expression of one or more genes in the array. This can occurin various biological contexts, as disclosed herein, for exampledevelopment of a protein kinase, methyltransferase, acyl-CoAdehydrogenase, short chain dehyrdogenase, reductase, acyltransferase,phosphatase, transferase, ATP-ase or synthase-associated or another27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or65577-associated disease or disorder, progression of protein kinase,methyltransferase, acyl-CoA dehydrogenase, short chain dehyrdogenase,reductase, acyltransferase, phosphatase, transferase, ATP-ase orsynthase-associated or another 27877, 18080, 14081, 32140, 50352, 16658,14223, 16002, 50566, 65552 or 65577-associated disease or disorder, andprocesses, such a cellular transformation associated with thephospholipase, serine carboxypeptidase, trypsin-like serine protease,aldehyde dehydrogenase, ubiquitin-protein ligase, protein kinase,hydrolase or matrix metalloproteinase-associated or another 27877,18080,-14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or65577-associated disease or disorder.

[0745] The array is also useful for ascertaining the effect of theexpression of a gene on the expression of other genes in the same cellor in different cells (e.g., acertaining the effect of 27877, 18080,14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577expression on the expression of other genes). This provides, forexample, for a selection of alternate molecular targets for therapeuticintervention if the ultimate or downstream target cannot be regulated.

[0746] The array is also useful for ascertaining differential expressionpatterns of one or more genes in normal and abnormal cells. Thisprovides a battery of genes (e.g., including 27877, 18080, 14081, 32140,50352, 16658, 14223, 16002, 50566, 65552 or 65577) that could serve as amolecular target for diagnosis or therapeutic intervention.

[0747] As used herein, a “target sequence” can be any DNA or amino acidsequence of six or more nucleotides or two or more amino acids. Askilled artisan can readily recognize that the longer a target sequenceis, the less likely a target sequence will be present as a randomoccurrence in the database. Typical sequence lengths of a targetsequence are from about 10 to 100 amino acids or from about 30 to 300nucleotide residues. However, it is well recognized that commerciallyimportant fragments, such as sequence fragments involved in geneexpression and protein processing, may be of shorter length.

[0748] Computer software is publicly available which allows a skilledartisan to access sequence information provided in a computer readablemedium for analysis and comparison to other sequences. A variety ofknown algorithms are disclosed publicly and a variety of commerciallyavailable software for conducting search means are and can be used inthe computer-based systems of the present invention. Examples of suchsoftware include, but are not limited to, MacPattern (EMBL), BLASTN andBLASTX (NCBI).

[0749] Thus, the invention features a-method of making a computerreadable record of a sequence of a 27877, 18080, 14081, 32140, 50352,16658, 14223, 16002, 50566, 65552 or 65577 sequence which includesrecording the sequence on a computer readable matrix. In a preferredembodiment the record includes one or more of the following:identification of an ORF; identification of a domain, region, or site;identification of the start of transcription; identification of thetranscription terminator; the full length amino acid sequence of theprotein, or a mature form thereof; the 5′ end of the translated region.

[0750] In another aspect, the invention features a method of analyzing asequence. The method-includes: providing a 27877, 18080, 14081, 32140,50352, 16658, 14223, 16002, 50566, 65552 or 65577 sequence, or record,in computer readable form; comparing a second sequence to the 27877,18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577sequence; thereby analyzing a sequence. Comparison can include comparingto sequences for sequence identity or determining if one sequence isincluded within the other, e.g., determining if the 27877, 18080, 14081,32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 sequenceincludes a sequence being compared. In a preferred embodiment the 27877,18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577or second sequence is stored on a first computer, e.g., at a first siteand the comparison is performed, read, or recorded on a second computer,e.g., at a second site. E.g., the 27877, 18080, 14081, 32140, 50352,16658, 14223, 16002, 50566, 65552 or 65577 or second sequence can bestored in a public or proprietary database in one computer, and theresults of the comparison performed, read, or recorded on a secondcomputer. In a preferred embodiment the record includes one or more ofthe following: identification of an ORF; identification of a domain,region, or site; identification of the start of transcription;identification of the transcription terminator; the full length aminoacid sequence of the protein, or a mature form thereof; the 5′ end ofthe translated region.

EXEMPLIFICATION Example 1

[0751] Tissue Distribution of 27877, 18080, 14081, 32140, 50352, 16658,14223, 16002, 50566, 65552 or 65577 mRNA

[0752] Northern blot hybridizations with various RNA samples can beperformed under standard conditions and washed under stringentconditions, i.e., 0.2×SSC at 65° C. A DNA probe corresponding to all ora portion of the 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577 cDNA (SEQ ID NO: 1, 3, 4, 6, 11, 13, 20, 22, 25,27, 29, 31, 35, 37, 38, 40, 41, 43, 73, 75, 76, 78, 86 or 88) or 27877,18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577cDNA can be used. The DNA was radioactively labeled with ³²P-dCTP usingthe Prime-It Kit (Stratagene, La Jolla, Calif.) according to theinstructions of the supplier. Filters containing mRNA from mousehematopoietic and endocrine tissues, and cancer cell lines (Clontech,Palo Alto, Calif.) can be probed in ExpressHyb hybridization solution(Clontech) and washed at high stringency according to manufacturer'srecommendations.

Example 2

[0753] Recombinant Expression of 27877, 18080, 14081, 32140, 50352,16658, 14223, 16002, 50566, 65552 or 65577 in Bacterial Cells

[0754] In this example, 27877, 18080, 14081, 32140, 50352, 16658, 14223,16002, 50566, 65552 or 65577 is expressed as a recombinantglutathione-S-transferase (GST) fusion polypeptide in E. coli and thefusion polypeptide is isolated and characterized. Specifically, 27877,18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577is fused to GST and this fusion polypeptide is expressed in E. coli,e.g., strain PEB199. Expression of the GST-27877, -18080, -14081,-32140, -50352, -16658, -14223, -16002, -50566, -65552 or -65577 fusionprotein in PEB 199 is induced with IPTG. The recombinant fusionpolypeptide is purified from crude bacterial lysates of the inducedPEB199 strain by affinity chromatography on glutathione beads. Usingpolyacrylamide gel electrophoretic analysis of the polypeptide purifiedfrom the bacterial lysates, the molecular weight of the resultant fusionpolypeptide is determined.

Example 3

[0755] Expression of Recombinant 27877, 18080, 14081, 32140, 50352,16658, 14223, 16002, 50566, 65552 or 65577 Protein in COS Cells

[0756] To express the 27877, 18080, 14081, 32140, 50352, 16658, 14223,16002, 50566, 65552 or 65577 gene in COS cells, the pcDNA/Amp vector byInvitrogen Corporation (San Diego, Calif.) is used. This vector containsan SV40 origin of replication, an ampicillin resistance gene, an E. colireplication origin, a CMV promoter followed by a polylinker region, andan SV40 intron and polyadenylation site. A DNA fragment encoding theentire 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566,65552 or 65577 protein and an HA tag (Wilson et al. (1984) Cell 37:767)or a FLAG tag fused in-frame to its 3′ end of the fragment is clonedinto the polylinker region of the vector, thereby placing the expressionof the recombinant protein under the control of the CMV promoter.

[0757] To construct the plasmid, the 27877, 18080, 14081, 32140, 50352,16658, 14223, 16002, 50566, 65552 or 65577 DNA sequence is amplified byPCR using two primers. The 5′ primer contains the restriction site ofinterest followed by approximately twenty nucleotides of the 27877,18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577coding sequence starting from the initiation codon; the 3′ end sequencecontains complementary sequences to the other restriction site ofinterest, a translation stop codon, the HA tag or FLAG tag and the last20 nucleotides of the 27877, 18080, 14081, 32140, 50352, 16658, 14223,16002, 50566, 65552 or 65577 coding sequence. The PCR amplified fragmentand the pCDNA/Amp vector are digested with the appropriate restrictionenzymes and the vector is dephosphorylated using the CIAP enzyme (NewEngland Biolabs, Beverly, Mass.). Preferably the two restriction siteschosen are different so that the 27877, 18080, 14081, 32140, 50352,16658, 14223, 16002, 50566, 65552 or 65577 gene is inserted in thecorrect orientation. The ligation mixture is transformed into E. colicells (strains HB101, DH5α, SURE, available from Stratagene CloningSystems, La Jolla, Calif., can be used), the transformed culture isplated on ampicillin media plates, and resistant colonies are selected.Plasmid DNA is isolated from transformants and examined by restrictionanalysis for the presence of the correct fragment.

[0758] COS cells are subsequently transfected with the 27877-, 18080-,14081-, 32140-, 50352-, 16658-, 14223-, 16002-, 50566-, 65552- or65577-pcDNA/Amp plasmid DNA using the calcium phosphate or calciumchloride co-precipitation methods, DEAE-dextran-mediated transfection,lipofection, or electroporation. Other suitable methods for transfectinghost cells can be found in Sambrook, J., Fritsh, E. F., and Maniatis, T.Molecular Cloning: A Laboratory Manual. 2nd, ed., Cold Spring HarborLaboratory, Cold Spring Harbor Laboratory Press, Cold Spring Harbor,N.Y., 1989. The expression of the 27877, 18080, 14081, 32140, 50352,16658, 14223, 16002, 50566, 65552 or 65577 polypeptide is detected byradiolabelling (³⁵S-methionine or ³⁵S-cysteine available from NEN,Boston, Mass., can be used) and immunoprecipitation (Harlow, E. andLane, D. Antibodies: A Laboratory Manual, Cold Spring Harbor LaboratoryPress, Cold Spring Harbor, N.Y., 1988) using an HA specific monoclonalantibody. Briefly, the cells are labeled for 8 hours with ³⁵S-methionine(or ³⁵S-cysteine). The culture media are then collected and the cellsare lysed using detergents (RIPA buffer, 150 mM NaCl, 1% NP-40, 0.1%SDS, 0.5% DOC, 50 mM Tris, pH 7.5). Both the cell lysate and the culturemedia are precipitated with an HA specific monoclonal antibody.Precipitated polypeptides are then analyzed by SDS-PAGE.

[0759] Alternatively, DNA containing the 27877, 18080, 14081, 32140,50352, 16658, 14223, 16002, 50566, 65552 or 65577 coding sequence iscloned directly into the polylinker of the pCDNA/Amp vector using theappropriate restriction sites. The resulting plasmid is transfected intoCOS cells in the manner described above, and the expression of the27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or65577 polypeptide is detected by radiolabelling and immunoprecipitationusing a 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566,65552 or 65577 specific monoclonal antibody.

Exmaple 4

[0760] TaqMan Analysis of 27877, 18080, 14081, 32140, 50352, 16658,14223, 16002, 50566, 65552 or 65577

[0761] Human 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577 expression was measured by TaqMan® quantitativePCR (Perkin Elmer Applied Biosystems) in cDNA prepared from a variety ofnormal and diseased (e.g., cancerous) human tissues or cell lines.

[0762] Probes were designed by PrimerExpress software (PE Biosystems)based on the sequence of the human 27877, 18080, 14081, 32140, 50352,16658, 14223, 16002, 50566, 65552 or 65577 gene. Each human 27877,18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577gene probe was labeled using FAM (6-carboxyfluorescein), and theβ2-microglobulin reference probe was labeled with a differentfluorescent dye, VIC. The differential labeling of the target gene andinternal reference gene thus enabled measurement in same well. Forwardand reverse primers and the probes for both β2-microglobulin and targetgene were added to the TaqMan® Universal PCR Master Mix (PE AppliedBiosystems). Although the final concentration of primer and probe couldvary, each was internally consistent within a given experiment. Atypical experiment contained 200 nM of forward and reverse primers plus100 nM probe for β-2 microglobulin and 600 nM forward and reverseprimers plus 200 nM probe for the target gene. TaqMan matrix experimentswere carried out on an ABI PRISM 7700 Sequence Detection System (PEApplied Biosystems). The thermal cycler conditions were as follows: holdfor 2 min at 50° C. and 10 min at 95° C., followed by two-step PCR for40 cycles of 95° C. for 15 sec followed by 60° C. for 1 min.

[0763] The following method was used to quantitatively calculate human27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or65577 gene expression in the various tissues relative to β-2microglobulin expression in the same tissue. The threshold cycle (Ct)value is defined as the cycle at which a statistically significantincrease in fluorescence is detected. A lower Ct value is indicative ofa higher mRNA concentration. The Ct value of the human 27877, 18080,14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 gene isnormalized by subtracting the Ct value of the β-2 microglobulin gene toobtain a _(Δ)Ct value using the following formula:_(Δ)Ct=Ct_(human 59914 and) 59921−Ct_(β-2 microglobulin). Expression isthen calibrated against a cDNA sample showing a comparatively low levelof expression of the human 27877, 18080, 14081, 32140, 50352, 16658,14223, 16002, 50566, 65552 or 65577 gene. The ₆₆Ct value for thecalibrator sample is then subtracted from _(Δ)Ct for each tissue sampleaccording to the following formula:

_(ΔΔ) Ct= _(Δ) Ct-_(sample)−_(Δ) Ct-_(calibrator).

[0764] Relative expression is then calculated using the arithmeticformula given by 2^(−ΔΔCt).

Example 5

[0765] In Situ Hybridization of 27877, 18080, 14081, 32140, 50352,16658, 14223, 16002, 50566, 65552 or 65577

[0766] The following describes the tissue distribution of 27877, 18080,14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 mRNA, asmay be determined by in situ hybridization analysis usingoligonucleotide probes based on the human G2RF sequence.

[0767] For in situ analysis, various tissues, e.g. tissues obtained frombrain, are first frozen on dry ice. Ten-micrometer-thick sections of thetissues are postfixed with 4% formaldehyde in DEPC treated IXphosphate-buffered saline at room temperature for 10 minutes beforebeing rinsed twice in DEPC 1X phosphate-buffered saline and once in 0.1M triethanolamine-HCl (pH 8.0). Following incubation in 0.25% aceticanhydride-0.1 M triethanolamine-HCl for 10 minutes, sections are rinsedin DEPC 2×SSC (1×SSC is 0.15M NaCl plus 0.015M sodium citrate). Tissueis then dehydrated through a series of ethanol washes, incubated in 100%chloroform for 5 minutes, and then rinsed in 100% ethanol for 1 minuteand 95% ethanol for 1 minute and allowed to air dry.

[0768] Hybridizations are performed with ³⁵S-radiolabeled (5×10⁷ cpm/ml)cRNA probes. Probes are incubated in the presence of a solutioncontaining 600 mM NaCl, 10 mM Tris (pH 7.5), 1 mM EDTA, 0.01% shearedsalmon sperm DNA, 0.01% yeast tRNA, 0.05% yeast total RNA type X1, 1×Denhardt's solution, 50% formamide, 10% dextran sulfate, 100 mMdithiothreitol, 0.1% sodium dodecyl sulfate (SDS), and 0.1% sodiumthiosulfate for 18 hours at 55° C.

[0769] After hybridization, slides are washed with 2×SSC. Sections arethen sequentially incubated at 37° C. in TNE (a solution containing 10mM Tris-HCl (pH 7.6), 500 mM NaCl, and 1 mM EDTA), for 10 minutes, inTNE with 10 μg of RNase A per ml for 30 minutes, and finally in TNE for10 minutes. Slides are then rinsed with 2×SSC at room temperature,washed with 2×SSC at 50° C. for 1 hour, washed with 0.2×SSC at 55° C.for 1 hour, and 0.2×SSC at 60° C. for 1 hour. Sections are thendehydrated rapidly through serial ethanol—0.3 M sodium acetateconcentrations before being air dried and exposed to Kodak Biomax MRscientific imaging film for 24 hours and subsequently dipped in NB-2photoemulsion and exposed at 4° C. for 7 days before being developed andcounter stained.

[0770] The contents of all references, patents and published patentapplications cited throughout this application are incorporated hereinby reference.

[0771] Equivalents

[0772] Those skilled in the art will recognize, or be able to ascertainusing no more than routine experimentation, many equivalents to thespecific embodiments of the invention described herein.

1 93 1 2981 DNA Homo sapiens CDS (202)...(2826) 1 cacgaggccg gcggcagaacgcagctgcgg cggctgcggg tctcgtgggg gcggagcggt 60 cgccgctgcc gccgcagctcgggtcgggat ttgaaagatt agaaacttcg ggtggagagg 120 gcggcggcgt tgaatgtgtggcggaagcgc tgggggtcac ggctccgcgc gccgccggac 180 agccggcggc gtctccacag catg aat tac ccg ggc cgc ggg tcc cca cgg 231 Met Asn Tyr Pro Gly Arg GlySer Pro Arg 1 5 10 agc ccc gag cat aac ggc cga ggc ggc ggc ggc ggc gcctgg gag ctg 279 Ser Pro Glu His Asn Gly Arg Gly Gly Gly Gly Gly Ala TrpGlu Leu 15 20 25 ggc tca gac gcg agg cca gcg ttc ggc ggc ggc gtc tgc tgcttc gag 327 Gly Ser Asp Ala Arg Pro Ala Phe Gly Gly Gly Val Cys Cys PheGlu 30 35 40 cac ctg ccc ggc ggg gac ccg gac gac ggc gac gtg ccc ctg gccctg 375 His Leu Pro Gly Gly Asp Pro Asp Asp Gly Asp Val Pro Leu Ala Leu45 50 55 ctg cgc ggg gaa ccc ggg ctg cat ttg gcg ccg ggc acc gac gac cac423 Leu Arg Gly Glu Pro Gly Leu His Leu Ala Pro Gly Thr Asp Asp His 6065 70 aac cac cac ctc gcg ctg gac ccc tgc ctc agt gac gag aac tat gac471 Asn His His Leu Ala Leu Asp Pro Cys Leu Ser Asp Glu Asn Tyr Asp 7580 85 90 ttt agc tcc gcc gag tcg ggc tcc tcg ctg cgc tac tac agc gag ggt519 Phe Ser Ser Ala Glu Ser Gly Ser Ser Leu Arg Tyr Tyr Ser Glu Gly 95100 105 gag agc ggc ggc ggc ggc ggc ggc agc tcc ttg tcg ctg cat ccg ccg567 Glu Ser Gly Gly Gly Gly Gly Gly Ser Ser Leu Ser Leu His Pro Pro 110115 120 cag cag cct ccg ctg gtc ccg acg aac tcg ggg ggc ggc ggc gcg aca615 Gln Gln Pro Pro Leu Val Pro Thr Asn Ser Gly Gly Gly Gly Ala Thr 125130 135 gga ggg tcc ccc ggg gaa agg aaa cgt acc cgg ctt ggc ggc ccg gcg663 Gly Gly Ser Pro Gly Glu Arg Lys Arg Thr Arg Leu Gly Gly Pro Ala 140145 150 gcc cgg cac cgc tat gag gta gtg acg gag ctg ggc ccg gag gag gta711 Ala Arg His Arg Tyr Glu Val Val Thr Glu Leu Gly Pro Glu Glu Val 155160 165 170 cgc tgg ttc tac aag gag gac aag aag acc tgg aag ccc ttc atcggc 759 Arg Trp Phe Tyr Lys Glu Asp Lys Lys Thr Trp Lys Pro Phe Ile Gly175 180 185 tac gac tcg ctc cgc atc gag ctc gcc ttc cgg acc ctg ctg cagacc 807 Tyr Asp Ser Leu Arg Ile Glu Leu Ala Phe Arg Thr Leu Leu Gln Thr190 195 200 acg ggt gcc cgg ccc cag ggc ggg gac cgg gac ggc gac cat gtgtgc 855 Thr Gly Ala Arg Pro Gln Gly Gly Asp Arg Asp Gly Asp His Val Cys205 210 215 tcc ccc acg agc cca gcc tcc agt tcc gga gaa gat gac gat gaggac 903 Ser Pro Thr Ser Pro Ala Ser Ser Ser Gly Glu Asp Asp Asp Glu Asp220 225 230 cgc gcc tgc ggc ttc tgc cag agt acg acg ggg cac gag ccg gagatg 951 Arg Ala Cys Gly Phe Cys Gln Ser Thr Thr Gly His Glu Pro Glu Met235 240 245 250 gtg gag ctt gtg aac atc gag cct gtg tgc gtg cgg ggc ggcctc tac 999 Val Glu Leu Val Asn Ile Glu Pro Val Cys Val Arg Gly Gly LeuTyr 255 260 265 gag gtg gat gtg acc caa gga gag tgc tac ccg gtg tac tggaac cag 1047 Glu Val Asp Val Thr Gln Gly Glu Cys Tyr Pro Val Tyr Trp AsnGln 270 275 280 gct gat aaa ata cca gta atg cgt gga cag tgg ttt att gacggc act 1095 Ala Asp Lys Ile Pro Val Met Arg Gly Gln Trp Phe Ile Asp GlyThr 285 290 295 tgg cag cct cta gaa gag gaa gaa agt aat tta att gag caagaa cat 1143 Trp Gln Pro Leu Glu Glu Glu Glu Ser Asn Leu Ile Glu Gln GluHis 300 305 310 ctc aat tgt ttt agg ggc cag cag atg cag gaa aat ttc gatatt gaa 1191 Leu Asn Cys Phe Arg Gly Gln Gln Met Gln Glu Asn Phe Asp IleGlu 315 320 325 330 gtg tca aaa tcc ata gat gga aaa gat gct gtt cat agtttc aag ttg 1239 Val Ser Lys Ser Ile Asp Gly Lys Asp Ala Val His Ser PheLys Leu 335 340 345 agt cga aac cat gtg gac tgg cac agt gtg gat gaa gtatat ctt tat 1287 Ser Arg Asn His Val Asp Trp His Ser Val Asp Glu Val TyrLeu Tyr 350 355 360 agt gat gca aca aca tct aaa att gca aga aca gtt acccaa aaa ctg 1335 Ser Asp Ala Thr Thr Ser Lys Ile Ala Arg Thr Val Thr GlnLys Leu 365 370 375 gga ttt tct aaa gca tca agt agt ggt acc aga ctt cataga ggt tat 1383 Gly Phe Ser Lys Ala Ser Ser Ser Gly Thr Arg Leu His ArgGly Tyr 380 385 390 gta gaa gaa gcc aca tta gaa gac aag cca tca cag actacc cat att 1431 Val Glu Glu Ala Thr Leu Glu Asp Lys Pro Ser Gln Thr ThrHis Ile 395 400 405 410 gta ttt gtt gtg cat ggc att ggg cag aaa atg gaccaa gga aga att 1479 Val Phe Val Val His Gly Ile Gly Gln Lys Met Asp GlnGly Arg Ile 415 420 425 atc aaa aat aca gct atg atg aga gaa gct gca agaaaa ata gaa gaa 1527 Ile Lys Asn Thr Ala Met Met Arg Glu Ala Ala Arg LysIle Glu Glu 430 435 440 agg cat ttt tcc aac cat gca aca cat gtt gaa tttctg cct gtt gag 1575 Arg His Phe Ser Asn His Ala Thr His Val Glu Phe LeuPro Val Glu 445 450 455 tgg cgg tca aaa ctt act ctt gat gga gac act gttgat tcc att act 1623 Trp Arg Ser Lys Leu Thr Leu Asp Gly Asp Thr Val AspSer Ile Thr 460 465 470 cct gac aaa gta cga ggt tta agg gat atg ctg aacagc agt gca atg 1671 Pro Asp Lys Val Arg Gly Leu Arg Asp Met Leu Asn SerSer Ala Met 475 480 485 490 gac ata atg tat tat act agt cca ctt tat agagat gaa cta gtt aaa 1719 Asp Ile Met Tyr Tyr Thr Ser Pro Leu Tyr Arg AspGlu Leu Val Lys 495 500 505 ggc ctt cag caa gag ctg aat cga ttg tat tccctt ttc tgt tct cgg 1767 Gly Leu Gln Gln Glu Leu Asn Arg Leu Tyr Ser LeuPhe Cys Ser Arg 510 515 520 aat cca gac ttt gaa gaa aaa ggg ggt aaa gtctca ata gta tca cat 1815 Asn Pro Asp Phe Glu Glu Lys Gly Gly Lys Val SerIle Val Ser His 525 530 535 tcc ttg gga tgt gta att act tat gac ata atgact ggc tgg aat cca 1863 Ser Leu Gly Cys Val Ile Thr Tyr Asp Ile Met ThrGly Trp Asn Pro 540 545 550 gtt cgg ctg tat gaa cag ttg ctg caa aag gaagaa gag ttg cct gat 1911 Val Arg Leu Tyr Glu Gln Leu Leu Gln Lys Glu GluGlu Leu Pro Asp 555 560 565 570 gaa cga tgg atg agc tat gaa gaa cga catctt ctt gat gaa ctc tat 1959 Glu Arg Trp Met Ser Tyr Glu Glu Arg His LeuLeu Asp Glu Leu Tyr 575 580 585 ata aca aaa cga cgg ctg aag gaa ata gaagaa cgg ctt cac gga ttg 2007 Ile Thr Lys Arg Arg Leu Lys Glu Ile Glu GluArg Leu His Gly Leu 590 595 600 aaa gca tca tct atg aca caa aca cct gcctta aaa ttt aag gtt gag 2055 Lys Ala Ser Ser Met Thr Gln Thr Pro Ala LeuLys Phe Lys Val Glu 605 610 615 aat ttc ttc tgt atg gga tcc cca tta gcagtt ttc ttg gcg ttg cgt 2103 Asn Phe Phe Cys Met Gly Ser Pro Leu Ala ValPhe Leu Ala Leu Arg 620 625 630 ggc atc cgc cca gga aat act gga agt caagac cat att ttg cct aga 2151 Gly Ile Arg Pro Gly Asn Thr Gly Ser Gln AspHis Ile Leu Pro Arg 635 640 645 650 gag att tgt aac cgg tta cta aat attttt cat cct aca gat cca gtg 2199 Glu Ile Cys Asn Arg Leu Leu Asn Ile PheHis Pro Thr Asp Pro Val 655 660 665 gct tat aga tta gaa cca tta ata ctgaaa cac tac agc aac att tca 2247 Ala Tyr Arg Leu Glu Pro Leu Ile Leu LysHis Tyr Ser Asn Ile Ser 670 675 680 cct gtc cag atc cac tgg tac aat acttca aat cct tta cct tat gaa 2295 Pro Val Gln Ile His Trp Tyr Asn Thr SerAsn Pro Leu Pro Tyr Glu 685 690 695 cat atg aag cca agc ttt ctc aac ccagct aaa gaa cct acc tca gtt 2343 His Met Lys Pro Ser Phe Leu Asn Pro AlaLys Glu Pro Thr Ser Val 700 705 710 tca gag aat gaa ggc att tca acc atacca agc cct gtg acc tca cca 2391 Ser Glu Asn Glu Gly Ile Ser Thr Ile ProSer Pro Val Thr Ser Pro 715 720 725 730 gtt ttg tcc cgc cga cac tat ggagaa tct ata aca aat ata ggc aaa 2439 Val Leu Ser Arg Arg His Tyr Gly GluSer Ile Thr Asn Ile Gly Lys 735 740 745 gca agc ata tta ggg gct gct agcatt gga aag gga ctt gga gga atg 2487 Ala Ser Ile Leu Gly Ala Ala Ser IleGly Lys Gly Leu Gly Gly Met 750 755 760 ttg ttc tca aga ttt gga cgt tcatct aca aca cag tca tct gaa aca 2535 Leu Phe Ser Arg Phe Gly Arg Ser SerThr Thr Gln Ser Ser Glu Thr 765 770 775 tca aaa gac tca atg gaa gat gagaag aag cca gtt gcc tca cct tct 2583 Ser Lys Asp Ser Met Glu Asp Glu LysLys Pro Val Ala Ser Pro Ser 780 785 790 gct acc acc gta ggg aca cag accctt cca cat agc agt tct ggc ttc 2631 Ala Thr Thr Val Gly Thr Gln Thr LeuPro His Ser Ser Ser Gly Phe 795 800 805 810 ctc gat tct gca ttg gag ttggat cac agg att gat ttt gaa ctc aga 2679 Leu Asp Ser Ala Leu Glu Leu AspHis Arg Ile Asp Phe Glu Leu Arg 815 820 825 gaa ggc ctt gtg gag agc cgctat tgg tca gct gtc acg tcg cat act 2727 Glu Gly Leu Val Glu Ser Arg TyrTrp Ser Ala Val Thr Ser His Thr 830 835 840 gcc tat tgg tca tcc ttg gatgtt gcc ctt ttt ctt tta acc ttc atg 2775 Ala Tyr Trp Ser Ser Leu Asp ValAla Leu Phe Leu Leu Thr Phe Met 845 850 855 tat aaa cat gag cac gat gatgat gca aaa ccc aat tta gat cca atc 2823 Tyr Lys His Glu His Asp Asp AspAla Lys Pro Asn Leu Asp Pro Ile 860 865 870 tga actcttgaag gacatgaatggcctaaaact gatttttttt tttttccgtt 2876 * aaaatgtgtg tgtcaagata cggagatttcagggttaaag tatatttcag ttttctttag 2936 ggcaacatat atttgaattt aaaagcactttatttaaaaa aaaaa 2981 2 874 PRT Homo sapiens 2 Met Asn Tyr Pro Gly ArgGly Ser Pro Arg Ser Pro Glu His Asn Gly 1 5 10 15 Arg Gly Gly Gly GlyGly Ala Trp Glu Leu Gly Ser Asp Ala Arg Pro 20 25 30 Ala Phe Gly Gly GlyVal Cys Cys Phe Glu His Leu Pro Gly Gly Asp 35 40 45 Pro Asp Asp Gly AspVal Pro Leu Ala Leu Leu Arg Gly Glu Pro Gly 50 55 60 Leu His Leu Ala ProGly Thr Asp Asp His Asn His His Leu Ala Leu 65 70 75 80 Asp Pro Cys LeuSer Asp Glu Asn Tyr Asp Phe Ser Ser Ala Glu Ser 85 90 95 Gly Ser Ser LeuArg Tyr Tyr Ser Glu Gly Glu Ser Gly Gly Gly Gly 100 105 110 Gly Gly SerSer Leu Ser Leu His Pro Pro Gln Gln Pro Pro Leu Val 115 120 125 Pro ThrAsn Ser Gly Gly Gly Gly Ala Thr Gly Gly Ser Pro Gly Glu 130 135 140 ArgLys Arg Thr Arg Leu Gly Gly Pro Ala Ala Arg His Arg Tyr Glu 145 150 155160 Val Val Thr Glu Leu Gly Pro Glu Glu Val Arg Trp Phe Tyr Lys Glu 165170 175 Asp Lys Lys Thr Trp Lys Pro Phe Ile Gly Tyr Asp Ser Leu Arg Ile180 185 190 Glu Leu Ala Phe Arg Thr Leu Leu Gln Thr Thr Gly Ala Arg ProGln 195 200 205 Gly Gly Asp Arg Asp Gly Asp His Val Cys Ser Pro Thr SerPro Ala 210 215 220 Ser Ser Ser Gly Glu Asp Asp Asp Glu Asp Arg Ala CysGly Phe Cys 225 230 235 240 Gln Ser Thr Thr Gly His Glu Pro Glu Met ValGlu Leu Val Asn Ile 245 250 255 Glu Pro Val Cys Val Arg Gly Gly Leu TyrGlu Val Asp Val Thr Gln 260 265 270 Gly Glu Cys Tyr Pro Val Tyr Trp AsnGln Ala Asp Lys Ile Pro Val 275 280 285 Met Arg Gly Gln Trp Phe Ile AspGly Thr Trp Gln Pro Leu Glu Glu 290 295 300 Glu Glu Ser Asn Leu Ile GluGln Glu His Leu Asn Cys Phe Arg Gly 305 310 315 320 Gln Gln Met Gln GluAsn Phe Asp Ile Glu Val Ser Lys Ser Ile Asp 325 330 335 Gly Lys Asp AlaVal His Ser Phe Lys Leu Ser Arg Asn His Val Asp 340 345 350 Trp His SerVal Asp Glu Val Tyr Leu Tyr Ser Asp Ala Thr Thr Ser 355 360 365 Lys IleAla Arg Thr Val Thr Gln Lys Leu Gly Phe Ser Lys Ala Ser 370 375 380 SerSer Gly Thr Arg Leu His Arg Gly Tyr Val Glu Glu Ala Thr Leu 385 390 395400 Glu Asp Lys Pro Ser Gln Thr Thr His Ile Val Phe Val Val His Gly 405410 415 Ile Gly Gln Lys Met Asp Gln Gly Arg Ile Ile Lys Asn Thr Ala Met420 425 430 Met Arg Glu Ala Ala Arg Lys Ile Glu Glu Arg His Phe Ser AsnHis 435 440 445 Ala Thr His Val Glu Phe Leu Pro Val Glu Trp Arg Ser LysLeu Thr 450 455 460 Leu Asp Gly Asp Thr Val Asp Ser Ile Thr Pro Asp LysVal Arg Gly 465 470 475 480 Leu Arg Asp Met Leu Asn Ser Ser Ala Met AspIle Met Tyr Tyr Thr 485 490 495 Ser Pro Leu Tyr Arg Asp Glu Leu Val LysGly Leu Gln Gln Glu Leu 500 505 510 Asn Arg Leu Tyr Ser Leu Phe Cys SerArg Asn Pro Asp Phe Glu Glu 515 520 525 Lys Gly Gly Lys Val Ser Ile ValSer His Ser Leu Gly Cys Val Ile 530 535 540 Thr Tyr Asp Ile Met Thr GlyTrp Asn Pro Val Arg Leu Tyr Glu Gln 545 550 555 560 Leu Leu Gln Lys GluGlu Glu Leu Pro Asp Glu Arg Trp Met Ser Tyr 565 570 575 Glu Glu Arg HisLeu Leu Asp Glu Leu Tyr Ile Thr Lys Arg Arg Leu 580 585 590 Lys Glu IleGlu Glu Arg Leu His Gly Leu Lys Ala Ser Ser Met Thr 595 600 605 Gln ThrPro Ala Leu Lys Phe Lys Val Glu Asn Phe Phe Cys Met Gly 610 615 620 SerPro Leu Ala Val Phe Leu Ala Leu Arg Gly Ile Arg Pro Gly Asn 625 630 635640 Thr Gly Ser Gln Asp His Ile Leu Pro Arg Glu Ile Cys Asn Arg Leu 645650 655 Leu Asn Ile Phe His Pro Thr Asp Pro Val Ala Tyr Arg Leu Glu Pro660 665 670 Leu Ile Leu Lys His Tyr Ser Asn Ile Ser Pro Val Gln Ile HisTrp 675 680 685 Tyr Asn Thr Ser Asn Pro Leu Pro Tyr Glu His Met Lys ProSer Phe 690 695 700 Leu Asn Pro Ala Lys Glu Pro Thr Ser Val Ser Glu AsnGlu Gly Ile 705 710 715 720 Ser Thr Ile Pro Ser Pro Val Thr Ser Pro ValLeu Ser Arg Arg His 725 730 735 Tyr Gly Glu Ser Ile Thr Asn Ile Gly LysAla Ser Ile Leu Gly Ala 740 745 750 Ala Ser Ile Gly Lys Gly Leu Gly GlyMet Leu Phe Ser Arg Phe Gly 755 760 765 Arg Ser Ser Thr Thr Gln Ser SerGlu Thr Ser Lys Asp Ser Met Glu 770 775 780 Asp Glu Lys Lys Pro Val AlaSer Pro Ser Ala Thr Thr Val Gly Thr 785 790 795 800 Gln Thr Leu Pro HisSer Ser Ser Gly Phe Leu Asp Ser Ala Leu Glu 805 810 815 Leu Asp His ArgIle Asp Phe Glu Leu Arg Glu Gly Leu Val Glu Ser 820 825 830 Arg Tyr TrpSer Ala Val Thr Ser His Thr Ala Tyr Trp Ser Ser Leu 835 840 845 Asp ValAla Leu Phe Leu Leu Thr Phe Met Tyr Lys His Glu His Asp 850 855 860 AspAsp Ala Lys Pro Asn Leu Asp Pro Ile 865 870 3 2622 DNA Homo sapiens CDS(1)...(2622) 3 atg aat tac ccg ggc cgc ggg tcc cca cgg agc ccc gag cataac ggc 48 Met Asn Tyr Pro Gly Arg Gly Ser Pro Arg Ser Pro Glu His AsnGly 1 5 10 15 cga ggc ggc ggc ggc ggc gcc tgg gag ctg ggc tca gac gcgagg cca 96 Arg Gly Gly Gly Gly Gly Ala Trp Glu Leu Gly Ser Asp Ala ArgPro 20 25 30 gcg ttc ggc ggc ggc gtc tgc tgc ttc gag cac ctg ccc ggc ggggac 144 Ala Phe Gly Gly Gly Val Cys Cys Phe Glu His Leu Pro Gly Gly Asp35 40 45 ccg gac gac ggc gac gtg ccc ctg gcc ctg ctg cgc ggg gaa ccc ggg192 Pro Asp Asp Gly Asp Val Pro Leu Ala Leu Leu Arg Gly Glu Pro Gly 5055 60 ctg cat ttg gcg ccg ggc acc gac gac cac aac cac cac ctc gcg ctg240 Leu His Leu Ala Pro Gly Thr Asp Asp His Asn His His Leu Ala Leu 6570 75 80 gac ccc tgc ctc agt gac gag aac tat gac ttt agc tcc gcc gag tcg288 Asp Pro Cys Leu Ser Asp Glu Asn Tyr Asp Phe Ser Ser Ala Glu Ser 8590 95 ggc tcc tcg ctg cgc tac tac agc gag ggt gag agc ggc ggc ggc ggc336 Gly Ser Ser Leu Arg Tyr Tyr Ser Glu Gly Glu Ser Gly Gly Gly Gly 100105 110 ggc ggc agc tcc ttg tcg ctg cat ccg ccg cag cag cct ccg ctg gtc384 Gly Gly Ser Ser Leu Ser Leu His Pro Pro Gln Gln Pro Pro Leu Val 115120 125 ccg acg aac tcg ggg ggc ggc ggc gcg aca gga ggg tcc ccc ggg gaa432 Pro Thr Asn Ser Gly Gly Gly Gly Ala Thr Gly Gly Ser Pro Gly Glu 130135 140 agg aaa cgt acc cgg ctt ggc ggc ccg gcg gcc cgg cac cgc tat gag480 Arg Lys Arg Thr Arg Leu Gly Gly Pro Ala Ala Arg His Arg Tyr Glu 145150 155 160 gta gtg acg gag ctg ggc ccg gag gag gta cgc tgg ttc tac aaggag 528 Val Val Thr Glu Leu Gly Pro Glu Glu Val Arg Trp Phe Tyr Lys Glu165 170 175 gac aag aag acc tgg aag ccc ttc atc ggc tac gac tcg ctc cgcatc 576 Asp Lys Lys Thr Trp Lys Pro Phe Ile Gly Tyr Asp Ser Leu Arg Ile180 185 190 gag ctc gcc ttc cgg acc ctg ctg cag acc acg ggt gcc cgg ccccag 624 Glu Leu Ala Phe Arg Thr Leu Leu Gln Thr Thr Gly Ala Arg Pro Gln195 200 205 ggc ggg gac cgg gac ggc gac cat gtg tgc tcc ccc acg agc ccagcc 672 Gly Gly Asp Arg Asp Gly Asp His Val Cys Ser Pro Thr Ser Pro Ala210 215 220 tcc agt tcc gga gaa gat gac gat gag gac cgc gcc tgc ggc ttctgc 720 Ser Ser Ser Gly Glu Asp Asp Asp Glu Asp Arg Ala Cys Gly Phe Cys225 230 235 240 cag agt acg acg ggg cac gag ccg gag atg gtg gag ctt gtgaac atc 768 Gln Ser Thr Thr Gly His Glu Pro Glu Met Val Glu Leu Val AsnIle 245 250 255 gag cct gtg tgc gtg cgg ggc ggc ctc tac gag gtg gat gtgacc caa 816 Glu Pro Val Cys Val Arg Gly Gly Leu Tyr Glu Val Asp Val ThrGln 260 265 270 gga gag tgc tac ccg gtg tac tgg aac cag gct gat aaa atacca gta 864 Gly Glu Cys Tyr Pro Val Tyr Trp Asn Gln Ala Asp Lys Ile ProVal 275 280 285 atg cgt gga cag tgg ttt att gac ggc act tgg cag cct ctagaa gag 912 Met Arg Gly Gln Trp Phe Ile Asp Gly Thr Trp Gln Pro Leu GluGlu 290 295 300 gaa gaa agt aat tta att gag caa gaa cat ctc aat tgt tttagg ggc 960 Glu Glu Ser Asn Leu Ile Glu Gln Glu His Leu Asn Cys Phe ArgGly 305 310 315 320 cag cag atg cag gaa aat ttc gat att gaa gtg tca aaatcc ata gat 1008 Gln Gln Met Gln Glu Asn Phe Asp Ile Glu Val Ser Lys SerIle Asp 325 330 335 gga aaa gat gct gtt cat agt ttc aag ttg agt cga aaccat gtg gac 1056 Gly Lys Asp Ala Val His Ser Phe Lys Leu Ser Arg Asn HisVal Asp 340 345 350 tgg cac agt gtg gat gaa gta tat ctt tat agt gat gcaaca aca tct 1104 Trp His Ser Val Asp Glu Val Tyr Leu Tyr Ser Asp Ala ThrThr Ser 355 360 365 aaa att gca aga aca gtt acc caa aaa ctg gga ttt tctaaa gca tca 1152 Lys Ile Ala Arg Thr Val Thr Gln Lys Leu Gly Phe Ser LysAla Ser 370 375 380 agt agt ggt acc aga ctt cat aga ggt tat gta gaa gaagcc aca tta 1200 Ser Ser Gly Thr Arg Leu His Arg Gly Tyr Val Glu Glu AlaThr Leu 385 390 395 400 gaa gac aag cca tca cag act acc cat att gta tttgtt gtg cat ggc 1248 Glu Asp Lys Pro Ser Gln Thr Thr His Ile Val Phe ValVal His Gly 405 410 415 att ggg cag aaa atg gac caa gga aga att atc aaaaat aca gct atg 1296 Ile Gly Gln Lys Met Asp Gln Gly Arg Ile Ile Lys AsnThr Ala Met 420 425 430 atg aga gaa gct gca aga aaa ata gaa gaa agg catttt tcc aac cat 1344 Met Arg Glu Ala Ala Arg Lys Ile Glu Glu Arg His PheSer Asn His 435 440 445 gca aca cat gtt gaa ttt ctg cct gtt gag tgg cggtca aaa ctt act 1392 Ala Thr His Val Glu Phe Leu Pro Val Glu Trp Arg SerLys Leu Thr 450 455 460 ctt gat gga gac act gtt gat tcc att act cct gacaaa gta cga ggt 1440 Leu Asp Gly Asp Thr Val Asp Ser Ile Thr Pro Asp LysVal Arg Gly 465 470 475 480 tta agg gat atg ctg aac agc agt gca atg gacata atg tat tat act 1488 Leu Arg Asp Met Leu Asn Ser Ser Ala Met Asp IleMet Tyr Tyr Thr 485 490 495 agt cca ctt tat aga gat gaa cta gtt aaa ggcctt cag caa gag ctg 1536 Ser Pro Leu Tyr Arg Asp Glu Leu Val Lys Gly LeuGln Gln Glu Leu 500 505 510 aat cga ttg tat tcc ctt ttc tgt tct cgg aatcca gac ttt gaa gaa 1584 Asn Arg Leu Tyr Ser Leu Phe Cys Ser Arg Asn ProAsp Phe Glu Glu 515 520 525 aaa ggg ggt aaa gtc tca ata gta tca cat tccttg gga tgt gta att 1632 Lys Gly Gly Lys Val Ser Ile Val Ser His Ser LeuGly Cys Val Ile 530 535 540 act tat gac ata atg act ggc tgg aat cca gttcgg ctg tat gaa cag 1680 Thr Tyr Asp Ile Met Thr Gly Trp Asn Pro Val ArgLeu Tyr Glu Gln 545 550 555 560 ttg ctg caa aag gaa gaa gag ttg cct gatgaa cga tgg atg agc tat 1728 Leu Leu Gln Lys Glu Glu Glu Leu Pro Asp GluArg Trp Met Ser Tyr 565 570 575 gaa gaa cga cat ctt ctt gat gaa ctc tatata aca aaa cga cgg ctg 1776 Glu Glu Arg His Leu Leu Asp Glu Leu Tyr IleThr Lys Arg Arg Leu 580 585 590 aag gaa ata gaa gaa cgg ctt cac gga ttgaaa gca tca tct atg aca 1824 Lys Glu Ile Glu Glu Arg Leu His Gly Leu LysAla Ser Ser Met Thr 595 600 605 caa aca cct gcc tta aaa ttt aag gtt gagaat ttc ttc tgt atg gga 1872 Gln Thr Pro Ala Leu Lys Phe Lys Val Glu AsnPhe Phe Cys Met Gly 610 615 620 tcc cca tta gca gtt ttc ttg gcg ttg cgtggc atc cgc cca gga aat 1920 Ser Pro Leu Ala Val Phe Leu Ala Leu Arg GlyIle Arg Pro Gly Asn 625 630 635 640 act gga agt caa gac cat att ttg cctaga gag att tgt aac cgg tta 1968 Thr Gly Ser Gln Asp His Ile Leu Pro ArgGlu Ile Cys Asn Arg Leu 645 650 655 cta aat att ttt cat cct aca gat ccagtg gct tat aga tta gaa cca 2016 Leu Asn Ile Phe His Pro Thr Asp Pro ValAla Tyr Arg Leu Glu Pro 660 665 670 tta ata ctg aaa cac tac agc aac atttca cct gtc cag atc cac tgg 2064 Leu Ile Leu Lys His Tyr Ser Asn Ile SerPro Val Gln Ile His Trp 675 680 685 tac aat act tca aat cct tta cct tatgaa cat atg aag cca agc ttt 2112 Tyr Asn Thr Ser Asn Pro Leu Pro Tyr GluHis Met Lys Pro Ser Phe 690 695 700 ctc aac cca gct aaa gaa cct acc tcagtt tca gag aat gaa ggc att 2160 Leu Asn Pro Ala Lys Glu Pro Thr Ser ValSer Glu Asn Glu Gly Ile 705 710 715 720 tca acc ata cca agc cct gtg acctca cca gtt ttg tcc cgc cga cac 2208 Ser Thr Ile Pro Ser Pro Val Thr SerPro Val Leu Ser Arg Arg His 725 730 735 tat gga gaa tct ata aca aat ataggc aaa gca agc ata tta ggg gct 2256 Tyr Gly Glu Ser Ile Thr Asn Ile GlyLys Ala Ser Ile Leu Gly Ala 740 745 750 gct agc att gga aag gga ctt ggagga atg ttg ttc tca aga ttt gga 2304 Ala Ser Ile Gly Lys Gly Leu Gly GlyMet Leu Phe Ser Arg Phe Gly 755 760 765 cgt tca tct aca aca cag tca tctgaa aca tca aaa gac tca atg gaa 2352 Arg Ser Ser Thr Thr Gln Ser Ser GluThr Ser Lys Asp Ser Met Glu 770 775 780 gat gag aag aag cca gtt gcc tcacct tct gct acc acc gta ggg aca 2400 Asp Glu Lys Lys Pro Val Ala Ser ProSer Ala Thr Thr Val Gly Thr 785 790 795 800 cag acc ctt cca cat agc agttct ggc ttc ctc gat tct gca ttg gag 2448 Gln Thr Leu Pro His Ser Ser SerGly Phe Leu Asp Ser Ala Leu Glu 805 810 815 ttg gat cac agg att gat tttgaa ctc aga gaa ggc ctt gtg gag agc 2496 Leu Asp His Arg Ile Asp Phe GluLeu Arg Glu Gly Leu Val Glu Ser 820 825 830 cgc tat tgg tca gct gtc acgtcg cat act gcc tat tgg tca tcc ttg 2544 Arg Tyr Trp Ser Ala Val Thr SerHis Thr Ala Tyr Trp Ser Ser Leu 835 840 845 gat gtt gcc ctt ttt ctt ttaacc ttc atg tat aaa cat gag cac gat 2592 Asp Val Ala Leu Phe Leu Leu ThrPhe Met Tyr Lys His Glu His Asp 850 855 860 gat gat gca aaa ccc aat ttagat cca atc 2622 Asp Asp Ala Lys Pro Asn Leu Asp Pro Ile 865 870 4 3065DNA Homo sapiens CDS (202)...(2910) 4 cacgaggccg gcggcagaac gcagctgcggcggctgcggg tctcgtgggg gcggagcggt 60 cgccgctgcc gccgcagctc gggtcgggatttgaaagatt agaaacttcg ggtggagagg 120 gcggcggcgt tgaatgtgtg gcggaagcgctgggggtcac ggctccgcgc gccgccggac 180 agccggcggc gtctccacag c atg aat tacccg ggc cgc ggg tcc cca cgg 231 Met Asn Tyr Pro Gly Arg Gly Ser Pro Arg1 5 10 agc ccc gag cat aac ggc cga ggc ggc ggc ggc ggc gcc tgg gag ctg279 Ser Pro Glu His Asn Gly Arg Gly Gly Gly Gly Gly Ala Trp Glu Leu 1520 25 ggc tca gac gcg agg cca gcg ttc ggc ggc ggc gtc tgc tgc ttc gag327 Gly Ser Asp Ala Arg Pro Ala Phe Gly Gly Gly Val Cys Cys Phe Glu 3035 40 cac ctg ccc ggc ggg gac ccg gac gac ggc gac gtg ccc ctg gcc ctg375 His Leu Pro Gly Gly Asp Pro Asp Asp Gly Asp Val Pro Leu Ala Leu 4550 55 ctg cgc ggg gaa ccc ggg ctg cat ttg gcg ccg ggc acc gac gac cac423 Leu Arg Gly Glu Pro Gly Leu His Leu Ala Pro Gly Thr Asp Asp His 6065 70 aac cac cac ctc gcg ctg gac ccc tgc ctc agt gac gag aac tat gac471 Asn His His Leu Ala Leu Asp Pro Cys Leu Ser Asp Glu Asn Tyr Asp 7580 85 90 ttt agc tcc gcc gag tcg ggc tcc tcg ctg cgc tac tac agc gag ggt519 Phe Ser Ser Ala Glu Ser Gly Ser Ser Leu Arg Tyr Tyr Ser Glu Gly 95100 105 gag agc ggc ggc ggc ggc ggc ggc agc tcc ttg tcg ctg cat ccg ccg567 Glu Ser Gly Gly Gly Gly Gly Gly Ser Ser Leu Ser Leu His Pro Pro 110115 120 cag cag cct ccg ctg gtc ccg acg aac tcg ggg ggc ggc ggc gcg aca615 Gln Gln Pro Pro Leu Val Pro Thr Asn Ser Gly Gly Gly Gly Ala Thr 125130 135 gga ggg tcc ccc ggg gaa agg aaa cgt acc cgg ctt ggc ggc ccg gcg663 Gly Gly Ser Pro Gly Glu Arg Lys Arg Thr Arg Leu Gly Gly Pro Ala 140145 150 gcc cgg cac cgc tat gag gta gtg acg gag ctg ggc ccg gag gag gta711 Ala Arg His Arg Tyr Glu Val Val Thr Glu Leu Gly Pro Glu Glu Val 155160 165 170 cgc tgg ttc tac aag gag gac aag aag acc tgg aag ccc ttc atcggc 759 Arg Trp Phe Tyr Lys Glu Asp Lys Lys Thr Trp Lys Pro Phe Ile Gly175 180 185 tac gac tcg ctc cgc atc gag ctc gcc ttc cgg acc ctg ctg cagacc 807 Tyr Asp Ser Leu Arg Ile Glu Leu Ala Phe Arg Thr Leu Leu Gln Thr190 195 200 acg ggt gcc cgg ccc cag ggc ggg gac cgg gac ggc gac cat gtgtgc 855 Thr Gly Ala Arg Pro Gln Gly Gly Asp Arg Asp Gly Asp His Val Cys205 210 215 tcc ccc acg agc cca gcc tcc agt tcc gga gaa gat gac gat gaggac 903 Ser Pro Thr Ser Pro Ala Ser Ser Ser Gly Glu Asp Asp Asp Glu Asp220 225 230 cgc gcc tgc ggc ttc tgc cag agt acg acg ggg cac gag ccg gagatg 951 Arg Ala Cys Gly Phe Cys Gln Ser Thr Thr Gly His Glu Pro Glu Met235 240 245 250 gtg gag ctt gtg aac atc gag cct gtg tgc gtg cgg ggc ggcctc tac 999 Val Glu Leu Val Asn Ile Glu Pro Val Cys Val Arg Gly Gly LeuTyr 255 260 265 gag gtg gat gtg acc caa gga gag tgc tac ccg gtg tac tggaac cag 1047 Glu Val Asp Val Thr Gln Gly Glu Cys Tyr Pro Val Tyr Trp AsnGln 270 275 280 gct gat aaa ata cca gta atg cgt gga cag tgg ttt att gacggc act 1095 Ala Asp Lys Ile Pro Val Met Arg Gly Gln Trp Phe Ile Asp GlyThr 285 290 295 tgg cag cct cta gaa gag gaa gaa agt aat tta att gag caagaa cat 1143 Trp Gln Pro Leu Glu Glu Glu Glu Ser Asn Leu Ile Glu Gln GluHis 300 305 310 ctc aat tgt ttt agg ggc cag cag atg cag gaa aat ttc gatatt gaa 1191 Leu Asn Cys Phe Arg Gly Gln Gln Met Gln Glu Asn Phe Asp IleGlu 315 320 325 330 gtg tca aaa tcc ata gat gga aaa gat gct gtt cat agtttc aag ttg 1239 Val Ser Lys Ser Ile Asp Gly Lys Asp Ala Val His Ser PheLys Leu 335 340 345 agt cga aac cat gtg gac tgg cac agt gtg gat gaa gtatat ctt tat 1287 Ser Arg Asn His Val Asp Trp His Ser Val Asp Glu Val TyrLeu Tyr 350 355 360 agt gat gca aca aca tct aaa att gca aga aca gtt acccaa aaa ctg 1335 Ser Asp Ala Thr Thr Ser Lys Ile Ala Arg Thr Val Thr GlnLys Leu 365 370 375 gga ttt tct aaa gca tca agt agt ggt acc aga ctt cataga ggt tat 1383 Gly Phe Ser Lys Ala Ser Ser Ser Gly Thr Arg Leu His ArgGly Tyr 380 385 390 gta gaa gaa gcc aca tta gaa gac aag cca tca cag actacc cat att 1431 Val Glu Glu Ala Thr Leu Glu Asp Lys Pro Ser Gln Thr ThrHis Ile 395 400 405 410 gta ttt gtt gtg cat ggc att ggg cag aaa atg gaccaa gga aga att 1479 Val Phe Val Val His Gly Ile Gly Gln Lys Met Asp GlnGly Arg Ile 415 420 425 atc aaa aat aca gct atg atg aga gaa gct gca agaaaa ata gaa gaa 1527 Ile Lys Asn Thr Ala Met Met Arg Glu Ala Ala Arg LysIle Glu Glu 430 435 440 agg cat ttt tcc aac cat gca aca cat gtt gaa tttctg cct gtt gag 1575 Arg His Phe Ser Asn His Ala Thr His Val Glu Phe LeuPro Val Glu 445 450 455 tgg cgg tca aaa ctt act ctt gat gga gac act gttgat tcc att act 1623 Trp Arg Ser Lys Leu Thr Leu Asp Gly Asp Thr Val AspSer Ile Thr 460 465 470 cct gac aaa gta cga ggt tta agg gat atg ctg aacagc agt gca atg 1671 Pro Asp Lys Val Arg Gly Leu Arg Asp Met Leu Asn SerSer Ala Met 475 480 485 490 gac ata atg tat tat act agt cca ctt tat agagat gaa cta gtt aaa 1719 Asp Ile Met Tyr Tyr Thr Ser Pro Leu Tyr Arg AspGlu Leu Val Lys 495 500 505 ggc ctt cag caa gag ctg aat cga ttg tat tccctt ttc tgt tct cgg 1767 Gly Leu Gln Gln Glu Leu Asn Arg Leu Tyr Ser LeuPhe Cys Ser Arg 510 515 520 aat cca gac ttt gaa gaa aaa ggg ggt aaa gtctca ata gta tca cat 1815 Asn Pro Asp Phe Glu Glu Lys Gly Gly Lys Val SerIle Val Ser His 525 530 535 tcc ttg gga tgt gta att act tat gac ata atgact ggc tgg aat cca 1863 Ser Leu Gly Cys Val Ile Thr Tyr Asp Ile Met ThrGly Trp Asn Pro 540 545 550 gtt cgg ctg tat gaa cag ttg ctg caa aag gaagaa gag ttg cct gat 1911 Val Arg Leu Tyr Glu Gln Leu Leu Gln Lys Glu GluGlu Leu Pro Asp 555 560 565 570 gaa cga tgg atg agc tat gaa gaa cga catctt ctt gat gaa ctc tat 1959 Glu Arg Trp Met Ser Tyr Glu Glu Arg His LeuLeu Asp Glu Leu Tyr 575 580 585 ata aca aaa cga cgg ctg aag gaa ata gaagaa cgg ctt cac gga ttg 2007 Ile Thr Lys Arg Arg Leu Lys Glu Ile Glu GluArg Leu His Gly Leu 590 595 600 aaa gca tca tct atg aca caa aca cct gcctta aaa ttt aag gtt gag 2055 Lys Ala Ser Ser Met Thr Gln Thr Pro Ala LeuLys Phe Lys Val Glu 605 610 615 aat ttc ttc tgt atg gga tcc cca tta gcagtt ttc ttg gcg ttg cgt 2103 Asn Phe Phe Cys Met Gly Ser Pro Leu Ala ValPhe Leu Ala Leu Arg 620 625 630 ggc atc cgc cca gga aat act gga agt caagac cat att ttg cct aga 2151 Gly Ile Arg Pro Gly Asn Thr Gly Ser Gln AspHis Ile Leu Pro Arg 635 640 645 650 gag att tgt aac cgg tta cta aat attttt cat cct aca gat cca gtg 2199 Glu Ile Cys Asn Arg Leu Leu Asn Ile PheHis Pro Thr Asp Pro Val 655 660 665 gct tat aga tta gaa cca tta ata ctgaaa cac tac agc aac att tca 2247 Ala Tyr Arg Leu Glu Pro Leu Ile Leu LysHis Tyr Ser Asn Ile Ser 670 675 680 cct gtc cag atc cac tgg tac aat acttca aat cct tta cct tat gaa 2295 Pro Val Gln Ile His Trp Tyr Asn Thr SerAsn Pro Leu Pro Tyr Glu 685 690 695 cat atg aag cca agc ttt ctc aac ccagct aaa gaa cct acc tca gtt 2343 His Met Lys Pro Ser Phe Leu Asn Pro AlaLys Glu Pro Thr Ser Val 700 705 710 tca gag aat gaa ggc att tca acc atacca agc cct gtg acc tca cca 2391 Ser Glu Asn Glu Gly Ile Ser Thr Ile ProSer Pro Val Thr Ser Pro 715 720 725 730 gtt ttg tcc cgc cga cac tat ggagaa tct ata aca aat ata ggc aaa 2439 Val Leu Ser Arg Arg His Tyr Gly GluSer Ile Thr Asn Ile Gly Lys 735 740 745 gca agc ata tta ggg gct gct agcatt gga aag gga ctt gga gga atg 2487 Ala Ser Ile Leu Gly Ala Ala Ser IleGly Lys Gly Leu Gly Gly Met 750 755 760 ttg ttc tca aga ttt gga cgt tcatct aca aca cag tca tct gaa aca 2535 Leu Phe Ser Arg Phe Gly Arg Ser SerThr Thr Gln Ser Ser Glu Thr 765 770 775 tca aaa gac tca atg gaa gat gagaag aag cca gtt gcc tca cct tct 2583 Ser Lys Asp Ser Met Glu Asp Glu LysLys Pro Val Ala Ser Pro Ser 780 785 790 gct acc acc gta ggg aca cag accctt cca cat agc agt tct ggc ttc 2631 Ala Thr Thr Val Gly Thr Gln Thr LeuPro His Ser Ser Ser Gly Phe 795 800 805 810 ctc gat tct gca tat ttc agactt caa gaa tcg ttc ttt aat ctc cca 2679 Leu Asp Ser Ala Tyr Phe Arg LeuGln Glu Ser Phe Phe Asn Leu Pro 815 820 825 caa ctt ctt ttt ccg gaa aatgta atg cag aat aaa gat aat gcc ctc 2727 Gln Leu Leu Phe Pro Glu Asn ValMet Gln Asn Lys Asp Asn Ala Leu 830 835 840 gtg gag ttg gat cac agg attgat ttt gaa ctc aga gaa ggc ctt gtg 2775 Val Glu Leu Asp His Arg Ile AspPhe Glu Leu Arg Glu Gly Leu Val 845 850 855 gag agc cgc tat tgg tca gctgtc acg tcg cat act gcc tat tgg tca 2823 Glu Ser Arg Tyr Trp Ser Ala ValThr Ser His Thr Ala Tyr Trp Ser 860 865 870 tcc ttg gat gtt gcc ctt tttctt tta acc ttc atg tat aaa cat gag 2871 Ser Leu Asp Val Ala Leu Phe LeuLeu Thr Phe Met Tyr Lys His Glu 875 880 885 890 cac gat gat gat gca aaaccc aat tta gat cca atc tga actcttgaag 2920 His Asp Asp Asp Ala Lys ProAsn Leu Asp Pro Ile * 895 900 gacatgaatg gcctaaaact gatttttttttttttccgtt aaaatgtgtg tgtcaagata 2980 cggagatttc agggttaaag tatatttcagttttctttag ggcaacatat atttgaattt 3040 aaaagcactt tatttaaaaa aaaaa 3065 5902 PRT Homo sapiens 5 Met Asn Tyr Pro Gly Arg Gly Ser Pro Arg Ser ProGlu His Asn Gly 1 5 10 15 Arg Gly Gly Gly Gly Gly Ala Trp Glu Leu GlySer Asp Ala Arg Pro 20 25 30 Ala Phe Gly Gly Gly Val Cys Cys Phe Glu HisLeu Pro Gly Gly Asp 35 40 45 Pro Asp Asp Gly Asp Val Pro Leu Ala Leu LeuArg Gly Glu Pro Gly 50 55 60 Leu His Leu Ala Pro Gly Thr Asp Asp His AsnHis His Leu Ala Leu 65 70 75 80 Asp Pro Cys Leu Ser Asp Glu Asn Tyr AspPhe Ser Ser Ala Glu Ser 85 90 95 Gly Ser Ser Leu Arg Tyr Tyr Ser Glu GlyGlu Ser Gly Gly Gly Gly 100 105 110 Gly Gly Ser Ser Leu Ser Leu His ProPro Gln Gln Pro Pro Leu Val 115 120 125 Pro Thr Asn Ser Gly Gly Gly GlyAla Thr Gly Gly Ser Pro Gly Glu 130 135 140 Arg Lys Arg Thr Arg Leu GlyGly Pro Ala Ala Arg His Arg Tyr Glu 145 150 155 160 Val Val Thr Glu LeuGly Pro Glu Glu Val Arg Trp Phe Tyr Lys Glu 165 170 175 Asp Lys Lys ThrTrp Lys Pro Phe Ile Gly Tyr Asp Ser Leu Arg Ile 180 185 190 Glu Leu AlaPhe Arg Thr Leu Leu Gln Thr Thr Gly Ala Arg Pro Gln 195 200 205 Gly GlyAsp Arg Asp Gly Asp His Val Cys Ser Pro Thr Ser Pro Ala 210 215 220 SerSer Ser Gly Glu Asp Asp Asp Glu Asp Arg Ala Cys Gly Phe Cys 225 230 235240 Gln Ser Thr Thr Gly His Glu Pro Glu Met Val Glu Leu Val Asn Ile 245250 255 Glu Pro Val Cys Val Arg Gly Gly Leu Tyr Glu Val Asp Val Thr Gln260 265 270 Gly Glu Cys Tyr Pro Val Tyr Trp Asn Gln Ala Asp Lys Ile ProVal 275 280 285 Met Arg Gly Gln Trp Phe Ile Asp Gly Thr Trp Gln Pro LeuGlu Glu 290 295 300 Glu Glu Ser Asn Leu Ile Glu Gln Glu His Leu Asn CysPhe Arg Gly 305 310 315 320 Gln Gln Met Gln Glu Asn Phe Asp Ile Glu ValSer Lys Ser Ile Asp 325 330 335 Gly Lys Asp Ala Val His Ser Phe Lys LeuSer Arg Asn His Val Asp 340 345 350 Trp His Ser Val Asp Glu Val Tyr LeuTyr Ser Asp Ala Thr Thr Ser 355 360 365 Lys Ile Ala Arg Thr Val Thr GlnLys Leu Gly Phe Ser Lys Ala Ser 370 375 380 Ser Ser Gly Thr Arg Leu HisArg Gly Tyr Val Glu Glu Ala Thr Leu 385 390 395 400 Glu Asp Lys Pro SerGln Thr Thr His Ile Val Phe Val Val His Gly 405 410 415 Ile Gly Gln LysMet Asp Gln Gly Arg Ile Ile Lys Asn Thr Ala Met 420 425 430 Met Arg GluAla Ala Arg Lys Ile Glu Glu Arg His Phe Ser Asn His 435 440 445 Ala ThrHis Val Glu Phe Leu Pro Val Glu Trp Arg Ser Lys Leu Thr 450 455 460 LeuAsp Gly Asp Thr Val Asp Ser Ile Thr Pro Asp Lys Val Arg Gly 465 470 475480 Leu Arg Asp Met Leu Asn Ser Ser Ala Met Asp Ile Met Tyr Tyr Thr 485490 495 Ser Pro Leu Tyr Arg Asp Glu Leu Val Lys Gly Leu Gln Gln Glu Leu500 505 510 Asn Arg Leu Tyr Ser Leu Phe Cys Ser Arg Asn Pro Asp Phe GluGlu 515 520 525 Lys Gly Gly Lys Val Ser Ile Val Ser His Ser Leu Gly CysVal Ile 530 535 540 Thr Tyr Asp Ile Met Thr Gly Trp Asn Pro Val Arg LeuTyr Glu Gln 545 550 555 560 Leu Leu Gln Lys Glu Glu Glu Leu Pro Asp GluArg Trp Met Ser Tyr 565 570 575 Glu Glu Arg His Leu Leu Asp Glu Leu TyrIle Thr Lys Arg Arg Leu 580 585 590 Lys Glu Ile Glu Glu Arg Leu His GlyLeu Lys Ala Ser Ser Met Thr 595 600 605 Gln Thr Pro Ala Leu Lys Phe LysVal Glu Asn Phe Phe Cys Met Gly 610 615 620 Ser Pro Leu Ala Val Phe LeuAla Leu Arg Gly Ile Arg Pro Gly Asn 625 630 635 640 Thr Gly Ser Gln AspHis Ile Leu Pro Arg Glu Ile Cys Asn Arg Leu 645 650 655 Leu Asn Ile PheHis Pro Thr Asp Pro Val Ala Tyr Arg Leu Glu Pro 660 665 670 Leu Ile LeuLys His Tyr Ser Asn Ile Ser Pro Val Gln Ile His Trp 675 680 685 Tyr AsnThr Ser Asn Pro Leu Pro Tyr Glu His Met Lys Pro Ser Phe 690 695 700 LeuAsn Pro Ala Lys Glu Pro Thr Ser Val Ser Glu Asn Glu Gly Ile 705 710 715720 Ser Thr Ile Pro Ser Pro Val Thr Ser Pro Val Leu Ser Arg Arg His 725730 735 Tyr Gly Glu Ser Ile Thr Asn Ile Gly Lys Ala Ser Ile Leu Gly Ala740 745 750 Ala Ser Ile Gly Lys Gly Leu Gly Gly Met Leu Phe Ser Arg PheGly 755 760 765 Arg Ser Ser Thr Thr Gln Ser Ser Glu Thr Ser Lys Asp SerMet Glu 770 775 780 Asp Glu Lys Lys Pro Val Ala Ser Pro Ser Ala Thr ThrVal Gly Thr 785 790 795 800 Gln Thr Leu Pro His Ser Ser Ser Gly Phe LeuAsp Ser Ala Tyr Phe 805 810 815 Arg Leu Gln Glu Ser Phe Phe Asn Leu ProGln Leu Leu Phe Pro Glu 820 825 830 Asn Val Met Gln Asn Lys Asp Asn AlaLeu Val Glu Leu Asp His Arg 835 840 845 Ile Asp Phe Glu Leu Arg Glu GlyLeu Val Glu Ser Arg Tyr Trp Ser 850 855 860 Ala Val Thr Ser His Thr AlaTyr Trp Ser Ser Leu Asp Val Ala Leu 865 870 875 880 Phe Leu Leu Thr PheMet Tyr Lys His Glu His Asp Asp Asp Ala Lys 885 890 895 Pro Asn Leu AspPro Ile 900 6 2706 DNA Homo sapiens CDS (1)...(2706) 6 atg aat tac ccgggc cgc ggg tcc cca cgg agc ccc gag cat aac ggc 48 Met Asn Tyr Pro GlyArg Gly Ser Pro Arg Ser Pro Glu His Asn Gly 1 5 10 15 cga ggc ggc ggcggc ggc gcc tgg gag ctg ggc tca gac gcg agg cca 96 Arg Gly Gly Gly GlyGly Ala Trp Glu Leu Gly Ser Asp Ala Arg Pro 20 25 30 gcg ttc ggc ggc ggcgtc tgc tgc ttc gag cac ctg ccc ggc ggg gac 144 Ala Phe Gly Gly Gly ValCys Cys Phe Glu His Leu Pro Gly Gly Asp 35 40 45 ccg gac gac ggc gac gtgccc ctg gcc ctg ctg cgc ggg gaa ccc ggg 192 Pro Asp Asp Gly Asp Val ProLeu Ala Leu Leu Arg Gly Glu Pro Gly 50 55 60 ctg cat ttg gcg ccg ggc accgac gac cac aac cac cac ctc gcg ctg 240 Leu His Leu Ala Pro Gly Thr AspAsp His Asn His His Leu Ala Leu 65 70 75 80 gac ccc tgc ctc agt gac gagaac tat gac ttt agc tcc gcc gag tcg 288 Asp Pro Cys Leu Ser Asp Glu AsnTyr Asp Phe Ser Ser Ala Glu Ser 85 90 95 ggc tcc tcg ctg cgc tac tac agcgag ggt gag agc ggc ggc ggc ggc 336 Gly Ser Ser Leu Arg Tyr Tyr Ser GluGly Glu Ser Gly Gly Gly Gly 100 105 110 ggc ggc agc tcc ttg tcg ctg catccg ccg cag cag cct ccg ctg gtc 384 Gly Gly Ser Ser Leu Ser Leu His ProPro Gln Gln Pro Pro Leu Val 115 120 125 ccg acg aac tcg ggg ggc ggc ggcgcg aca gga ggg tcc ccc ggg gaa 432 Pro Thr Asn Ser Gly Gly Gly Gly AlaThr Gly Gly Ser Pro Gly Glu 130 135 140 agg aaa cgt acc cgg ctt ggc ggcccg gcg gcc cgg cac cgc tat gag 480 Arg Lys Arg Thr Arg Leu Gly Gly ProAla Ala Arg His Arg Tyr Glu 145 150 155 160 gta gtg acg gag ctg ggc ccggag gag gta cgc tgg ttc tac aag gag 528 Val Val Thr Glu Leu Gly Pro GluGlu Val Arg Trp Phe Tyr Lys Glu 165 170 175 gac aag aag acc tgg aag cccttc atc ggc tac gac tcg ctc cgc atc 576 Asp Lys Lys Thr Trp Lys Pro PheIle Gly Tyr Asp Ser Leu Arg Ile 180 185 190 gag ctc gcc ttc cgg acc ctgctg cag acc acg ggt gcc cgg ccc cag 624 Glu Leu Ala Phe Arg Thr Leu LeuGln Thr Thr Gly Ala Arg Pro Gln 195 200 205 ggc ggg gac cgg gac ggc gaccat gtg tgc tcc ccc acg agc cca gcc 672 Gly Gly Asp Arg Asp Gly Asp HisVal Cys Ser Pro Thr Ser Pro Ala 210 215 220 tcc agt tcc gga gaa gat gacgat gag gac cgc gcc tgc ggc ttc tgc 720 Ser Ser Ser Gly Glu Asp Asp AspGlu Asp Arg Ala Cys Gly Phe Cys 225 230 235 240 cag agt acg acg ggg cacgag ccg gag atg gtg gag ctt gtg aac atc 768 Gln Ser Thr Thr Gly His GluPro Glu Met Val Glu Leu Val Asn Ile 245 250 255 gag cct gtg tgc gtg cggggc ggc ctc tac gag gtg gat gtg acc caa 816 Glu Pro Val Cys Val Arg GlyGly Leu Tyr Glu Val Asp Val Thr Gln 260 265 270 gga gag tgc tac ccg gtgtac tgg aac cag gct gat aaa ata cca gta 864 Gly Glu Cys Tyr Pro Val TyrTrp Asn Gln Ala Asp Lys Ile Pro Val 275 280 285 atg cgt gga cag tgg tttatt gac ggc act tgg cag cct cta gaa gag 912 Met Arg Gly Gln Trp Phe IleAsp Gly Thr Trp Gln Pro Leu Glu Glu 290 295 300 gaa gaa agt aat tta attgag caa gaa cat ctc aat tgt ttt agg ggc 960 Glu Glu Ser Asn Leu Ile GluGln Glu His Leu Asn Cys Phe Arg Gly 305 310 315 320 cag cag atg cag gaaaat ttc gat att gaa gtg tca aaa tcc ata gat 1008 Gln Gln Met Gln Glu AsnPhe Asp Ile Glu Val Ser Lys Ser Ile Asp 325 330 335 gga aaa gat gct gttcat agt ttc aag ttg agt cga aac cat gtg gac 1056 Gly Lys Asp Ala Val HisSer Phe Lys Leu Ser Arg Asn His Val Asp 340 345 350 tgg cac agt gtg gatgaa gta tat ctt tat agt gat gca aca aca tct 1104 Trp His Ser Val Asp GluVal Tyr Leu Tyr Ser Asp Ala Thr Thr Ser 355 360 365 aaa att gca aga acagtt acc caa aaa ctg gga ttt tct aaa gca tca 1152 Lys Ile Ala Arg Thr ValThr Gln Lys Leu Gly Phe Ser Lys Ala Ser 370 375 380 agt agt ggt acc agactt cat aga ggt tat gta gaa gaa gcc aca tta 1200 Ser Ser Gly Thr Arg LeuHis Arg Gly Tyr Val Glu Glu Ala Thr Leu 385 390 395 400 gaa gac aag ccatca cag act acc cat att gta ttt gtt gtg cat ggc 1248 Glu Asp Lys Pro SerGln Thr Thr His Ile Val Phe Val Val His Gly 405 410 415 att ggg cag aaaatg gac caa gga aga att atc aaa aat aca gct atg 1296 Ile Gly Gln Lys MetAsp Gln Gly Arg Ile Ile Lys Asn Thr Ala Met 420 425 430 atg aga gaa gctgca aga aaa ata gaa gaa agg cat ttt tcc aac cat 1344 Met Arg Glu Ala AlaArg Lys Ile Glu Glu Arg His Phe Ser Asn His 435 440 445 gca aca cat gttgaa ttt ctg cct gtt gag tgg cgg tca aaa ctt act 1392 Ala Thr His Val GluPhe Leu Pro Val Glu Trp Arg Ser Lys Leu Thr 450 455 460 ctt gat gga gacact gtt gat tcc att act cct gac aaa gta cga ggt 1440 Leu Asp Gly Asp ThrVal Asp Ser Ile Thr Pro Asp Lys Val Arg Gly 465 470 475 480 tta agg gatatg ctg aac agc agt gca atg gac ata atg tat tat act 1488 Leu Arg Asp MetLeu Asn Ser Ser Ala Met Asp Ile Met Tyr Tyr Thr 485 490 495 agt cca ctttat aga gat gaa cta gtt aaa ggc ctt cag caa gag ctg 1536 Ser Pro Leu TyrArg Asp Glu Leu Val Lys Gly Leu Gln Gln Glu Leu 500 505 510 aat cga ttgtat tcc ctt ttc tgt tct cgg aat cca gac ttt gaa gaa 1584 Asn Arg Leu TyrSer Leu Phe Cys Ser Arg Asn Pro Asp Phe Glu Glu 515 520 525 aaa ggg ggtaaa gtc tca ata gta tca cat tcc ttg gga tgt gta att 1632 Lys Gly Gly LysVal Ser Ile Val Ser His Ser Leu Gly Cys Val Ile 530 535 540 act tat gacata atg act ggc tgg aat cca gtt cgg ctg tat gaa cag 1680 Thr Tyr Asp IleMet Thr Gly Trp Asn Pro Val Arg Leu Tyr Glu Gln 545 550 555 560 ttg ctgcaa aag gaa gaa gag ttg cct gat gaa cga tgg atg agc tat 1728 Leu Leu GlnLys Glu Glu Glu Leu Pro Asp Glu Arg Trp Met Ser Tyr 565 570 575 gaa gaacga cat ctt ctt gat gaa ctc tat ata aca aaa cga cgg ctg 1776 Glu Glu ArgHis Leu Leu Asp Glu Leu Tyr Ile Thr Lys Arg Arg Leu 580 585 590 aag gaaata gaa gaa cgg ctt cac gga ttg aaa gca tca tct atg aca 1824 Lys Glu IleGlu Glu Arg Leu His Gly Leu Lys Ala Ser Ser Met Thr 595 600 605 caa acacct gcc tta aaa ttt aag gtt gag aat ttc ttc tgt atg gga 1872 Gln Thr ProAla Leu Lys Phe Lys Val Glu Asn Phe Phe Cys Met Gly 610 615 620 tcc ccatta gca gtt ttc ttg gcg ttg cgt ggc atc cgc cca gga aat 1920 Ser Pro LeuAla Val Phe Leu Ala Leu Arg Gly Ile Arg Pro Gly Asn 625 630 635 640 actgga agt caa gac cat att ttg cct aga gag att tgt aac cgg tta 1968 Thr GlySer Gln Asp His Ile Leu Pro Arg Glu Ile Cys Asn Arg Leu 645 650 655 ctaaat att ttt cat cct aca gat cca gtg gct tat aga tta gaa cca 2016 Leu AsnIle Phe His Pro Thr Asp Pro Val Ala Tyr Arg Leu Glu Pro 660 665 670 ttaata ctg aaa cac tac agc aac att tca cct gtc cag atc cac tgg 2064 Leu IleLeu Lys His Tyr Ser Asn Ile Ser Pro Val Gln Ile His Trp 675 680 685 tacaat act tca aat cct tta cct tat gaa cat atg aag cca agc ttt 2112 Tyr AsnThr Ser Asn Pro Leu Pro Tyr Glu His Met Lys Pro Ser Phe 690 695 700 ctcaac cca gct aaa gaa cct acc tca gtt tca gag aat gaa ggc att 2160 Leu AsnPro Ala Lys Glu Pro Thr Ser Val Ser Glu Asn Glu Gly Ile 705 710 715 720tca acc ata cca agc cct gtg acc tca cca gtt ttg tcc cgc cga cac 2208 SerThr Ile Pro Ser Pro Val Thr Ser Pro Val Leu Ser Arg Arg His 725 730 735tat gga gaa tct ata aca aat ata ggc aaa gca agc ata tta ggg gct 2256 TyrGly Glu Ser Ile Thr Asn Ile Gly Lys Ala Ser Ile Leu Gly Ala 740 745 750gct agc att gga aag gga ctt gga gga atg ttg ttc tca aga ttt gga 2304 AlaSer Ile Gly Lys Gly Leu Gly Gly Met Leu Phe Ser Arg Phe Gly 755 760 765cgt tca tct aca aca cag tca tct gaa aca tca aaa gac tca atg gaa 2352 ArgSer Ser Thr Thr Gln Ser Ser Glu Thr Ser Lys Asp Ser Met Glu 770 775 780gat gag aag aag cca gtt gcc tca cct tct gct acc acc gta ggg aca 2400 AspGlu Lys Lys Pro Val Ala Ser Pro Ser Ala Thr Thr Val Gly Thr 785 790 795800 cag acc ctt cca cat agc agt tct ggc ttc ctc gat tct gca tat ttc 2448Gln Thr Leu Pro His Ser Ser Ser Gly Phe Leu Asp Ser Ala Tyr Phe 805 810815 aga ctt caa gaa tcg ttc ttt aat ctc cca caa ctt ctt ttt ccg gaa 2496Arg Leu Gln Glu Ser Phe Phe Asn Leu Pro Gln Leu Leu Phe Pro Glu 820 825830 aat gta atg cag aat aaa gat aat gcc ctc gtg gag ttg gat cac agg 2544Asn Val Met Gln Asn Lys Asp Asn Ala Leu Val Glu Leu Asp His Arg 835 840845 att gat ttt gaa ctc aga gaa ggc ctt gtg gag agc cgc tat tgg tca 2592Ile Asp Phe Glu Leu Arg Glu Gly Leu Val Glu Ser Arg Tyr Trp Ser 850 855860 gct gtc acg tcg cat act gcc tat tgg tca tcc ttg gat gtt gcc ctt 2640Ala Val Thr Ser His Thr Ala Tyr Trp Ser Ser Leu Asp Val Ala Leu 865 870875 880 ttt ctt tta acc ttc atg tat aaa cat gag cac gat gat gat gca aaa2688 Phe Leu Leu Thr Phe Met Tyr Lys His Glu His Asp Asp Asp Ala Lys 885890 895 ccc aat tta gat cca atc 2706 Pro Asn Leu Asp Pro Ile 900 7 2625DNA Bos taurus 7 atgaattacc cgggccatgg gtctccgcgg agctccgagc gtaacggcggccggggcggc 60 gacggcgccg cctgggagct gggctcggac acggaacccg cgttcgggggcagcgtctgc 120 cgcttcgacc acctgccagt cggggagcct ggcgatgacg aggtgcccctggccctgctg 180 cgcggggagc ccgggctgca cttggcgccg ggagcggagg accacaaccatcacctggcg 240 ctggacccct gcctcagtga cgataactat gacttcagct cggccgagtcgggctcctcg 300 ctgcgctact acagcgaggg cgagagtgga ggcggcggca gctcctcgtcgctgcacccg 360 cctcagcagc cgctggtccc gtcgaactcg gggggcggcg gggcggctggaggaggcccc 420 ggtgagagga agcgcacccg gcccggcggc gcggccgccc ggcacagatacgaggtggtg 480 acggagctgg gcccggagga ggtgcgctgg ttctacaagg aggacaagaagacctggaag 540 cccttcatcg gctacgactc gctccgcatc gagcttgcct tccgaacgctactgcaggcc 600 acgggggccc gagcccgggc ccaagacccg gacggcgacc atgtgtgcggcccggcctca 660 cccgcgggtc cggcctccag ctccgtggag gacgaagacg aggaccgcgtctgcggcttc 720 tgcccgcgca ttgcgggcca cgggcgcgag atggaggagc tggtgaacatcgagcgggtg 780 tgtgtgcggg gcggcctcta cgaggtggat gtgacccaag gagaatgctacccggtgtac 840 tggaaccagt ctgataaaat accagtaatg cgtggacagt ggtttattgatggtacctgg 900 cagccactag aagaagaaga aagtaattta attgagcaag aacatcttagccgttttaga 960 ggacagcaga tgcaggaaag ttttgatatt gaagtgtcga aacccatagatggaaaagat 1020 gctattcata gtttcaaatt gagtcgaaac cacgtggact ggcacagtgtggatgaagta 1080 tatctttata gtgatgcaac aacatccaaa attgcaagaa cagttactcaaaaactggga 1140 ttttctaaag catcaagtag tgggaccaga cttcatagag gttatgtagaagaagcgaca 1200 ttagaagaca agccatctca gactacccat atcgtatttg ttgtgcatggcattggacag 1260 aaaatggacc aaggaagaat tatcaaaaat actgccatga tgagagaggctgcaagaaaa 1320 atagaagaaa ggcatttttc caaccatgca acacatgttg aatttctgcctgttgagtgg 1380 cggtcaaaac ttactcttga tggagacact gttgattcca ttactccagacaaagtgcga 1440 ggtttaaggg atatgttaaa cagcagtgca atggacataa tgtattatactagcccactg 1500 tatagagatg aactagttaa aggccttcag caagagctca atcgattatattcccttttc 1560 tgttcccgga atccaaactt tgaggaaaaa gggggtaaag tctcaatagtgtcacattcc 1620 ttgggatgtg tgatcactta tgacataatg actggctgga atccagttcgactctatgaa 1680 cagttgctgc agaaggaaga agagttgcct gatgaacgat ggatgagctacgaagaacgt 1740 catcttcttg atgaactcta tataacaaaa cgacggctac gagaaattgaagaacggcta 1800 catggattga aagcatcatc tatgacacaa acacctgcct taaaatttaaggttgaaaat 1860 ttcttctgta tgggatcccc actagcagtt tttttggcac tgcgtggcatccgcccagga 1920 aacactggaa gtcaagacca tattttgccc agagagattt gtaaccgattactaaacatt 1980 ttccatccaa cagatccagt ggcttataga ttagaaccat taatactgaaacactacagc 2040 aacatttcac ctgtgcagat ccactggtat aatacatcca atcctctaccttatgagtat 2100 atgaagccaa gctttcttca cccagcgaaa gatcctacct caatttcagagaatgaaggc 2160 atctcaacaa taccaagccc tgtgacttcg ccagtcttgt ctcgccgacactatggggaa 2220 tctataacaa atataggcaa agcaagcata ttaggggctg caagcattggaaagggactt 2280 ggaggaatgt tgttctcaag atttggacgt tcatctgcat cacagccatctgagacatca 2340 agggactcca tagaagacga gaagaagcca gttgcctccc cgcccatgaccaccgtggca 2400 acgcagaccc ttccacacag cagttctggc tttcttgact ctgcattggaactggatcac 2460 agaattgact ttgaactcag agaaggcctt gtggagagcc gctattggtcagctgtcacg 2520 tcgcatactg cctattggtc atccttggat gttgccctct tcctgttaaccttcatgtac 2580 aaacacgagc acgataataa tgtgaaaccc agtttagatc cagtc 2625 8875 PRT Bos taurus 8 Met Asn Tyr Pro Gly His Gly Ser Pro Arg Ser Ser GluArg Asn Gly 1 5 10 15 Gly Arg Gly Gly Asp Gly Ala Ala Trp Glu Leu GlySer Asp Thr Glu 20 25 30 Pro Ala Phe Gly Gly Ser Val Cys Arg Phe Asp HisLeu Pro Val Gly 35 40 45 Glu Pro Gly Asp Asp Glu Val Pro Leu Ala Leu LeuArg Gly Glu Pro 50 55 60 Gly Leu His Leu Ala Pro Gly Ala Glu Asp His AsnHis His Leu Ala 65 70 75 80 Leu Asp Pro Cys Leu Ser Asp Asp Asn Tyr AspPhe Ser Ser Ala Glu 85 90 95 Ser Gly Ser Ser Leu Arg Tyr Tyr Ser Glu GlyGlu Ser Gly Gly Gly 100 105 110 Gly Ser Ser Ser Ser Leu His Pro Pro GlnGln Pro Leu Val Pro Ser 115 120 125 Asn Ser Gly Gly Gly Gly Ala Ala GlyGly Gly Pro Gly Glu Arg Lys 130 135 140 Arg Thr Arg Pro Gly Gly Ala AlaAla Arg His Arg Tyr Glu Val Val 145 150 155 160 Thr Glu Leu Gly Pro GluGlu Val Arg Trp Phe Tyr Lys Glu Asp Lys 165 170 175 Lys Thr Trp Lys ProPhe Ile Gly Tyr Asp Ser Leu Arg Ile Glu Leu 180 185 190 Ala Phe Arg ThrLeu Leu Gln Ala Thr Gly Ala Arg Ala Arg Ala Gln 195 200 205 Asp Pro AspGly Asp His Val Cys Gly Pro Ala Ser Pro Ala Gly Pro 210 215 220 Ala SerSer Ser Val Glu Asp Glu Asp Glu Asp Arg Val Cys Gly Phe 225 230 235 240Cys Pro Arg Ile Ala Gly His Gly Arg Glu Met Glu Glu Leu Val Asn 245 250255 Ile Glu Arg Val Cys Val Arg Gly Gly Leu Tyr Glu Val Asp Val Thr 260265 270 Gln Gly Glu Cys Tyr Pro Val Tyr Trp Asn Gln Ser Asp Lys Ile Pro275 280 285 Val Met Arg Gly Gln Trp Phe Ile Asp Gly Thr Trp Gln Pro LeuGlu 290 295 300 Glu Glu Glu Ser Asn Leu Ile Glu Gln Glu His Leu Ser ArgPhe Arg 305 310 315 320 Gly Gln Gln Met Gln Glu Ser Phe Asp Ile Glu ValSer Lys Pro Ile 325 330 335 Asp Gly Lys Asp Ala Ile His Ser Phe Lys LeuSer Arg Asn His Val 340 345 350 Asp Trp His Ser Val Asp Glu Val Tyr LeuTyr Ser Asp Ala Thr Thr 355 360 365 Ser Lys Ile Ala Arg Thr Val Thr GlnLys Leu Gly Phe Ser Lys Ala 370 375 380 Ser Ser Ser Gly Thr Arg Leu HisArg Gly Tyr Val Glu Glu Ala Thr 385 390 395 400 Leu Glu Asp Lys Pro SerGln Thr Thr His Ile Val Phe Val Val His 405 410 415 Gly Ile Gly Gln LysMet Asp Gln Gly Arg Ile Ile Lys Asn Thr Ala 420 425 430 Met Met Arg GluAla Ala Arg Lys Ile Glu Glu Arg His Phe Ser Asn 435 440 445 His Ala ThrHis Val Glu Phe Leu Pro Val Glu Trp Arg Ser Lys Leu 450 455 460 Thr LeuAsp Gly Asp Thr Val Asp Ser Ile Thr Pro Asp Lys Val Arg 465 470 475 480Gly Leu Arg Asp Met Leu Asn Ser Ser Ala Met Asp Ile Met Tyr Tyr 485 490495 Thr Ser Pro Leu Tyr Arg Asp Glu Leu Val Lys Gly Leu Gln Gln Glu 500505 510 Leu Asn Arg Leu Tyr Ser Leu Phe Cys Ser Arg Asn Pro Asn Phe Glu515 520 525 Glu Lys Gly Gly Lys Val Ser Ile Val Ser His Ser Leu Gly CysVal 530 535 540 Ile Thr Tyr Asp Ile Met Thr Gly Trp Asn Pro Val Arg LeuTyr Glu 545 550 555 560 Gln Leu Leu Gln Lys Glu Glu Glu Leu Pro Asp GluArg Trp Met Ser 565 570 575 Tyr Glu Glu Arg His Leu Leu Asp Glu Leu TyrIle Thr Lys Arg Arg 580 585 590 Leu Arg Glu Ile Glu Glu Arg Leu His GlyLeu Lys Ala Ser Ser Met 595 600 605 Thr Gln Thr Pro Ala Leu Lys Phe LysVal Glu Asn Phe Phe Cys Met 610 615 620 Gly Ser Pro Leu Ala Val Phe LeuAla Leu Arg Gly Ile Arg Pro Gly 625 630 635 640 Asn Thr Gly Ser Gln AspHis Ile Leu Pro Arg Glu Ile Cys Asn Arg 645 650 655 Leu Leu Asn Ile PheHis Pro Thr Asp Pro Val Ala Tyr Arg Leu Glu 660 665 670 Pro Leu Ile LeuLys His Tyr Ser Asn Ile Ser Pro Val Gln Ile His 675 680 685 Trp Tyr AsnThr Ser Asn Pro Leu Pro Tyr Glu Tyr Met Lys Pro Ser 690 695 700 Phe LeuHis Pro Ala Lys Asp Pro Thr Ser Ile Ser Glu Asn Glu Gly 705 710 715 720Ile Ser Thr Ile Pro Ser Pro Val Thr Ser Pro Val Leu Ser Arg Arg 725 730735 His Tyr Gly Glu Ser Ile Thr Asn Ile Gly Lys Ala Ser Ile Leu Gly 740745 750 Ala Ala Ser Ile Gly Lys Gly Leu Gly Gly Met Leu Phe Ser Arg Phe755 760 765 Gly Arg Ser Ser Ala Ser Gln Pro Ser Glu Thr Ser Arg Asp SerIle 770 775 780 Glu Asp Glu Lys Lys Pro Val Ala Ser Pro Pro Met Thr ThrVal Ala 785 790 795 800 Thr Gln Thr Leu Pro His Ser Ser Ser Gly Phe LeuAsp Ser Ala Leu 805 810 815 Glu Leu Asp His Arg Ile Asp Phe Glu Leu ArgGlu Gly Leu Val Glu 820 825 830 Ser Arg Tyr Trp Ser Ala Val Thr Ser HisThr Ala Tyr Trp Ser Ser 835 840 845 Leu Asp Val Ala Leu Phe Leu Leu ThrPhe Met Tyr Lys His Glu His 850 855 860 Asp Asn Asn Val Lys Pro Ser LeuAsp Pro Val 865 870 875 9 5 PRT Artificial Sequence Consensus amino acidsequence 9 Ser His Ser Leu Gly 1 5 10 5 PRT Artificial SequenceConsensus amino acid sequence 10 Xaa Xaa Ser Xaa Gly 1 5 11 1921 DNAHomo sapiens CDS (33)...(1391) 11 cctgttgctg atgctgccgt gcggtacttg tcatg gag ctg gca ctg cgg cgc 53 Met Glu Leu Ala Leu Arg Arg 1 5 tct cccgtc ccg cgg tgg ttg ctg ctg ctg ccg ctg ctg ctg ggc ctg 101 Ser Pro ValPro Arg Trp Leu Leu Leu Leu Pro Leu Leu Leu Gly Leu 10 15 20 aac gca ggagct gtc att gac tgg ccc aca gag gag ggc aag gaa gta 149 Asn Ala Gly AlaVal Ile Asp Trp Pro Thr Glu Glu Gly Lys Glu Val 25 30 35 tgg gat tat gtgacg gtc cgc aag gat gcc tac atg ttc tgg tgg ctc 197 Trp Asp Tyr Val ThrVal Arg Lys Asp Ala Tyr Met Phe Trp Trp Leu 40 45 50 55 tat tat gcc accaac tcc tgc aag aac ttc tca gaa ctg ccc ctg gtc 245 Tyr Tyr Ala Thr AsnSer Cys Lys Asn Phe Ser Glu Leu Pro Leu Val 60 65 70 atg tgg ctt cag ggcggt cca ggc ggt tct agc act gga ttt gga aac 293 Met Trp Leu Gln Gly GlyPro Gly Gly Ser Ser Thr Gly Phe Gly Asn 75 80 85 ttt gag gaa att ggg cccctt gac agt gat ctc aaa cca cgg aaa acc 341 Phe Glu Glu Ile Gly Pro LeuAsp Ser Asp Leu Lys Pro Arg Lys Thr 90 95 100 acc tgg ctc cag gct gccagt ctc cta ttt gtg gat aat ccc gtg ggc 389 Thr Trp Leu Gln Ala Ala SerLeu Leu Phe Val Asp Asn Pro Val Gly 105 110 115 act ggg ttc agt tat gtgaat ggt agt ggt gcc tat gcc aag gac ctg 437 Thr Gly Phe Ser Tyr Val AsnGly Ser Gly Ala Tyr Ala Lys Asp Leu 120 125 130 135 gct atg gtg gct tcagac atg atg gtt ctc ctg aag acc ttc ttc agt 485 Ala Met Val Ala Ser AspMet Met Val Leu Leu Lys Thr Phe Phe Ser 140 145 150 tgc cac aaa gaa ttccag aca gtt cca ttc tac att ttc tca gag tcc 533 Cys His Lys Glu Phe GlnThr Val Pro Phe Tyr Ile Phe Ser Glu Ser 155 160 165 tat gga gga aaa atggca gct ggc att ggt cta gag ctt tat aag gcc 581 Tyr Gly Gly Lys Met AlaAla Gly Ile Gly Leu Glu Leu Tyr Lys Ala 170 175 180 att cag cga ggg accatc aag tgc aac ttt gcg ggg gtt gcc ttg ggt 629 Ile Gln Arg Gly Thr IleLys Cys Asn Phe Ala Gly Val Ala Leu Gly 185 190 195 gat tcc tgg atc tccccc gtg gat tcg gtg ctc tcc tgg gga cct tac 677 Asp Ser Trp Ile Ser ProVal Asp Ser Val Leu Ser Trp Gly Pro Tyr 200 205 210 215 ctg tac agc atgtct ctt ctc gaa gac aaa ggt ctg gca gag gtg tct 725 Leu Tyr Ser Met SerLeu Leu Glu Asp Lys Gly Leu Ala Glu Val Ser 220 225 230 aag gtt gca gagcaa gta ctg aat gcc gta aat aag ggg ctc tac aga 773 Lys Val Ala Glu GlnVal Leu Asn Ala Val Asn Lys Gly Leu Tyr Arg 235 240 245 gag gcc aca gagctg tgg ggg aaa gca gaa atg atc att gaa cag aac 821 Glu Ala Thr Glu LeuTrp Gly Lys Ala Glu Met Ile Ile Glu Gln Asn 250 255 260 aca gat ggg gtgaac ttc tat aac atc tta act aaa agc act ccc acg 869 Thr Asp Gly Val AsnPhe Tyr Asn Ile Leu Thr Lys Ser Thr Pro Thr 265 270 275 tct aca atg gagtcg agt cta gaa ttc aca cag agc cac cta gtt tgt 917 Ser Thr Met Glu SerSer Leu Glu Phe Thr Gln Ser His Leu Val Cys 280 285 290 295 ctt tgt cagcgc cac gtg aga cac cta caa cga gat gcc tta agc cag 965 Leu Cys Gln ArgHis Val Arg His Leu Gln Arg Asp Ala Leu Ser Gln 300 305 310 ctc atg aatggc ccc atc aga aag aag ctc aaa att att cct gag gat 1013 Leu Met Asn GlyPro Ile Arg Lys Lys Leu Lys Ile Ile Pro Glu Asp 315 320 325 caa tcc tgggga ggc cag gct acc aac gtc ttt gtg aac atg gag gag 1061 Gln Ser Trp GlyGly Gln Ala Thr Asn Val Phe Val Asn Met Glu Glu 330 335 340 gac ttc atgaag cca gtc att agc att gtg gac gag ttg ctg gag gca 1109 Asp Phe Met LysPro Val Ile Ser Ile Val Asp Glu Leu Leu Glu Ala 345 350 355 ggg atc aacgtg acg gtg tat aat gga cag ctg gat ctc atc gta gat 1157 Gly Ile Asn ValThr Val Tyr Asn Gly Gln Leu Asp Leu Ile Val Asp 360 365 370 375 acc atgggt cag gag gcc tgg gtg cgg aaa ctg aag tgg cca gaa ctg 1205 Thr Met GlyGln Glu Ala Trp Val Arg Lys Leu Lys Trp Pro Glu Leu 380 385 390 cct aaattc agt cag ctg aag tgg aag gcc ctg tac agt gac cct aaa 1253 Pro Lys PheSer Gln Leu Lys Trp Lys Ala Leu Tyr Ser Asp Pro Lys 395 400 405 tct ttggaa aca tct gct ttt gtc aag tcc tac aag aac ctt gct ttc 1301 Ser Leu GluThr Ser Ala Phe Val Lys Ser Tyr Lys Asn Leu Ala Phe 410 415 420 tac tggatt ctg aaa gct ggt cat atg gtt cct tct gac caa ggg gac 1349 Tyr Trp IleLeu Lys Ala Gly His Met Val Pro Ser Asp Gln Gly Asp 425 430 435 atg gctctg aag atg atg aga ctg gtg act cag caa gaa tag 1391 Met Ala Leu Lys MetMet Arg Leu Val Thr Gln Gln Glu * 440 445 450 gatggatggg gctggagatgagctggtttg gccttggggc acagagctga gctgaggccg 1451 ctgaagctgt aggaagcgccattcttccct gtatctaact ggggctgtga tcaagaaggt 1511 tctgaccagc ttctgcagaggataaaatca ttgtctctgg aggcaatttg gaaattattt 1571 ctgcttctta aaaaaacctaagatttttta aaaaattgat ttgttttgat caaaataaag 1631 gatgataata gatattattttttcttatga cagaagcaaa tgatgtgatt tatagaaaaa 1691 ctgggaaata caggtacccaaagagtaaat caacatctgt ataccccctt cccaggggta 1751 agcactgtta ccaatttagcatatgtcctt gcagaatttt tttttctata tatacatata 1811 tattttttac caaaatgaatcattactcta tgttgtttta ctatttgttt gacatatcag 1871 tatatctgaa acaccttttcatgtcaataa atgttcttct ctaacattaa 1921 12 452 PRT Homo sapiens 12 Met GluLeu Ala Leu Arg Arg Ser Pro Val Pro Arg Trp Leu Leu Leu 1 5 10 15 LeuPro Leu Leu Leu Gly Leu Asn Ala Gly Ala Val Ile Asp Trp Pro 20 25 30 ThrGlu Glu Gly Lys Glu Val Trp Asp Tyr Val Thr Val Arg Lys Asp 35 40 45 AlaTyr Met Phe Trp Trp Leu Tyr Tyr Ala Thr Asn Ser Cys Lys Asn 50 55 60 PheSer Glu Leu Pro Leu Val Met Trp Leu Gln Gly Gly Pro Gly Gly 65 70 75 80Ser Ser Thr Gly Phe Gly Asn Phe Glu Glu Ile Gly Pro Leu Asp Ser 85 90 95Asp Leu Lys Pro Arg Lys Thr Thr Trp Leu Gln Ala Ala Ser Leu Leu 100 105110 Phe Val Asp Asn Pro Val Gly Thr Gly Phe Ser Tyr Val Asn Gly Ser 115120 125 Gly Ala Tyr Ala Lys Asp Leu Ala Met Val Ala Ser Asp Met Met Val130 135 140 Leu Leu Lys Thr Phe Phe Ser Cys His Lys Glu Phe Gln Thr ValPro 145 150 155 160 Phe Tyr Ile Phe Ser Glu Ser Tyr Gly Gly Lys Met AlaAla Gly Ile 165 170 175 Gly Leu Glu Leu Tyr Lys Ala Ile Gln Arg Gly ThrIle Lys Cys Asn 180 185 190 Phe Ala Gly Val Ala Leu Gly Asp Ser Trp IleSer Pro Val Asp Ser 195 200 205 Val Leu Ser Trp Gly Pro Tyr Leu Tyr SerMet Ser Leu Leu Glu Asp 210 215 220 Lys Gly Leu Ala Glu Val Ser Lys ValAla Glu Gln Val Leu Asn Ala 225 230 235 240 Val Asn Lys Gly Leu Tyr ArgGlu Ala Thr Glu Leu Trp Gly Lys Ala 245 250 255 Glu Met Ile Ile Glu GlnAsn Thr Asp Gly Val Asn Phe Tyr Asn Ile 260 265 270 Leu Thr Lys Ser ThrPro Thr Ser Thr Met Glu Ser Ser Leu Glu Phe 275 280 285 Thr Gln Ser HisLeu Val Cys Leu Cys Gln Arg His Val Arg His Leu 290 295 300 Gln Arg AspAla Leu Ser Gln Leu Met Asn Gly Pro Ile Arg Lys Lys 305 310 315 320 LeuLys Ile Ile Pro Glu Asp Gln Ser Trp Gly Gly Gln Ala Thr Asn 325 330 335Val Phe Val Asn Met Glu Glu Asp Phe Met Lys Pro Val Ile Ser Ile 340 345350 Val Asp Glu Leu Leu Glu Ala Gly Ile Asn Val Thr Val Tyr Asn Gly 355360 365 Gln Leu Asp Leu Ile Val Asp Thr Met Gly Gln Glu Ala Trp Val Arg370 375 380 Lys Leu Lys Trp Pro Glu Leu Pro Lys Phe Ser Gln Leu Lys TrpLys 385 390 395 400 Ala Leu Tyr Ser Asp Pro Lys Ser Leu Glu Thr Ser AlaPhe Val Lys 405 410 415 Ser Tyr Lys Asn Leu Ala Phe Tyr Trp Ile Leu LysAla Gly His Met 420 425 430 Val Pro Ser Asp Gln Gly Asp Met Ala Leu LysMet Met Arg Leu Val 435 440 445 Thr Gln Gln Glu 450 13 1359 DNA Homosapiens CDS (1)...(1359) 13 atg gag ctg gca ctg cgg cgc tct ccc gtc ccgcgg tgg ttg ctg ctg 48 Met Glu Leu Ala Leu Arg Arg Ser Pro Val Pro ArgTrp Leu Leu Leu 1 5 10 15 ctg ccg ctg ctg ctg ggc ctg aac gca gga gctgtc att gac tgg ccc 96 Leu Pro Leu Leu Leu Gly Leu Asn Ala Gly Ala ValIle Asp Trp Pro 20 25 30 aca gag gag ggc aag gaa gta tgg gat tat gtg acggtc cgc aag gat 144 Thr Glu Glu Gly Lys Glu Val Trp Asp Tyr Val Thr ValArg Lys Asp 35 40 45 gcc tac atg ttc tgg tgg ctc tat tat gcc acc aac tcctgc aag aac 192 Ala Tyr Met Phe Trp Trp Leu Tyr Tyr Ala Thr Asn Ser CysLys Asn 50 55 60 ttc tca gaa ctg ccc ctg gtc atg tgg ctt cag ggc ggt ccaggc ggt 240 Phe Ser Glu Leu Pro Leu Val Met Trp Leu Gln Gly Gly Pro GlyGly 65 70 75 80 tct agc act gga ttt gga aac ttt gag gaa att ggg ccc cttgac agt 288 Ser Ser Thr Gly Phe Gly Asn Phe Glu Glu Ile Gly Pro Leu AspSer 85 90 95 gat ctc aaa cca cgg aaa acc acc tgg ctc cag gct gcc agt ctccta 336 Asp Leu Lys Pro Arg Lys Thr Thr Trp Leu Gln Ala Ala Ser Leu Leu100 105 110 ttt gtg gat aat ccc gtg ggc act ggg ttc agt tat gtg aat ggtagt 384 Phe Val Asp Asn Pro Val Gly Thr Gly Phe Ser Tyr Val Asn Gly Ser115 120 125 ggt gcc tat gcc aag gac ctg gct atg gtg gct tca gac atg atggtt 432 Gly Ala Tyr Ala Lys Asp Leu Ala Met Val Ala Ser Asp Met Met Val130 135 140 ctc ctg aag acc ttc ttc agt tgc cac aaa gaa ttc cag aca gttcca 480 Leu Leu Lys Thr Phe Phe Ser Cys His Lys Glu Phe Gln Thr Val Pro145 150 155 160 ttc tac att ttc tca gag tcc tat gga gga aaa atg gca gctggc att 528 Phe Tyr Ile Phe Ser Glu Ser Tyr Gly Gly Lys Met Ala Ala GlyIle 165 170 175 ggt cta gag ctt tat aag gcc att cag cga ggg acc atc aagtgc aac 576 Gly Leu Glu Leu Tyr Lys Ala Ile Gln Arg Gly Thr Ile Lys CysAsn 180 185 190 ttt gcg ggg gtt gcc ttg ggt gat tcc tgg atc tcc ccc gtggat tcg 624 Phe Ala Gly Val Ala Leu Gly Asp Ser Trp Ile Ser Pro Val AspSer 195 200 205 gtg ctc tcc tgg gga cct tac ctg tac agc atg tct ctt ctcgaa gac 672 Val Leu Ser Trp Gly Pro Tyr Leu Tyr Ser Met Ser Leu Leu GluAsp 210 215 220 aaa ggt ctg gca gag gtg tct aag gtt gca gag caa gta ctgaat gcc 720 Lys Gly Leu Ala Glu Val Ser Lys Val Ala Glu Gln Val Leu AsnAla 225 230 235 240 gta aat aag ggg ctc tac aga gag gcc aca gag ctg tggggg aaa gca 768 Val Asn Lys Gly Leu Tyr Arg Glu Ala Thr Glu Leu Trp GlyLys Ala 245 250 255 gaa atg atc att gaa cag aac aca gat ggg gtg aac ttctat aac atc 816 Glu Met Ile Ile Glu Gln Asn Thr Asp Gly Val Asn Phe TyrAsn Ile 260 265 270 tta act aaa agc act ccc acg tct aca atg gag tcg agtcta gaa ttc 864 Leu Thr Lys Ser Thr Pro Thr Ser Thr Met Glu Ser Ser LeuGlu Phe 275 280 285 aca cag agc cac cta gtt tgt ctt tgt cag cgc cac gtgaga cac cta 912 Thr Gln Ser His Leu Val Cys Leu Cys Gln Arg His Val ArgHis Leu 290 295 300 caa cga gat gcc tta agc cag ctc atg aat ggc ccc atcaga aag aag 960 Gln Arg Asp Ala Leu Ser Gln Leu Met Asn Gly Pro Ile ArgLys Lys 305 310 315 320 ctc aaa att att cct gag gat caa tcc tgg gga ggccag gct acc aac 1008 Leu Lys Ile Ile Pro Glu Asp Gln Ser Trp Gly Gly GlnAla Thr Asn 325 330 335 gtc ttt gtg aac atg gag gag gac ttc atg aag ccagtc att agc att 1056 Val Phe Val Asn Met Glu Glu Asp Phe Met Lys Pro ValIle Ser Ile 340 345 350 gtg gac gag ttg ctg gag gca ggg atc aac gtg acggtg tat aat gga 1104 Val Asp Glu Leu Leu Glu Ala Gly Ile Asn Val Thr ValTyr Asn Gly 355 360 365 cag ctg gat ctc atc gta gat acc atg ggt cag gaggcc tgg gtg cgg 1152 Gln Leu Asp Leu Ile Val Asp Thr Met Gly Gln Glu AlaTrp Val Arg 370 375 380 aaa ctg aag tgg cca gaa ctg cct aaa ttc agt cagctg aag tgg aag 1200 Lys Leu Lys Trp Pro Glu Leu Pro Lys Phe Ser Gln LeuLys Trp Lys 385 390 395 400 gcc ctg tac agt gac cct aaa tct ttg gaa acatct gct ttt gtc aag 1248 Ala Leu Tyr Ser Asp Pro Lys Ser Leu Glu Thr SerAla Phe Val Lys 405 410 415 tcc tac aag aac ctt gct ttc tac tgg att ctgaaa gct ggt cat atg 1296 Ser Tyr Lys Asn Leu Ala Phe Tyr Trp Ile Leu LysAla Gly His Met 420 425 430 gtt cct tct gac caa ggg gac atg gct ctg aagatg atg aga ctg gtg 1344 Val Pro Ser Asp Gln Gly Asp Met Ala Leu Lys MetMet Arg Leu Val 435 440 445 act cag caa gaa tag 1359 Thr Gln Gln Glu *450 14 209 PRT Homo sapiens VARIANT (22)...(24) Xaa = Any Amino Acid 14Tyr Leu Thr Val Asn Asp Thr His Gly Lys Asn Leu Phe Tyr Trp Phe 1 5 1015 Phe Glu Ser Arg Asn Xaa Xaa Xaa Asp Pro Lys Gln Asp Pro Val Val 20 2530 Leu Trp Leu Asn Gly Gly Pro Gly Cys Ser Ser Leu Leu Phe Tyr Glu 35 4045 Asn Gly Pro Phe Ser Ile Ser Ser Asp Gly Ser Lys Ser Leu Pro Ser 50 5560 Leu Ser Leu Asn Pro Tyr Ser Trp Asn Asn Val Ala Asn Met Ile Tyr 65 7075 80 Leu Asp Gln Pro Val Gly Val Gly Phe Ser Tyr Ser Asp Ser Asp Asp 8590 95 Asp Tyr Thr Thr Thr Asn Asp Val Glu Ala Ala Lys Asp Leu Tyr Asn100 105 110 Phe Leu Gln Asp Phe Phe Gln Leu Phe Pro Glu Leu Leu Lys AsnAsp 115 120 125 Phe Tyr Ile Ala Gly Glu Ser Tyr Ala Gly His Tyr Ile ProThr Phe 130 135 140 Ala Ser Glu Ile Val Gln Gly Asn Lys Lys Asn Pro GlyPro Asn Ile 145 150 155 160 Asn Leu Lys Gly Leu Ala Ile Gly Asn Gly LeuThr Asp Pro Leu Ile 165 170 175 Gln Tyr Asn Ala Tyr Val Pro Phe Ala TyrGlu His Gly Gly Glu Leu 180 185 190 Ser Val Leu Ile Ser Glu Glu Tyr SerLys Ile Ser Lys Ser Phe Pro 195 200 205 Arg 15 119 PRT Homo sapiens 15Val Tyr Gln Lys Phe Leu Asp Thr Gly Asp Trp Met Arg Ser Phe Leu 1 5 1015 Val Lys Leu Leu Ser Leu Leu Glu Gln Gly Tyr Arg Val Leu Ile Tyr 20 2530 Ala Gly Asp Leu Asp Met Ile Cys Asn Trp Leu Gly Asn Glu Ala Trp 35 4045 Val Asn Ser Leu Glu Trp Ser Gly Lys Lys Gln Phe Gln Ala Ser Ser 50 5560 Trp Arg Pro Trp Leu Val Asp Gly Ala Asp Ser Glu Gln Val Ala Gly 65 7075 80 Phe Val Lys Thr Tyr Glu Lys His Leu Thr Phe Leu Thr Val Arg Gly 8590 95 Ala Gly His Met Val Pro Tyr Asp Lys Pro Gln Ala Ala Leu Gln Met100 105 110 Val Lys Arg Trp Ile Ala Gly 115 16 8 PRT Artificial SequenceConsensus amino acid sequence 16 Xaa Xaa Xaa Glu Ser Tyr Xaa Xaa 1 5 1718 PRT Artificial Sequence Consensus amino acid sequence 17 Xaa Xaa XaaXaa Xaa Xaa Xaa Xaa Xaa Xaa His Xaa Xaa Pro Xaa Xaa 1 5 10 15 Xaa Xaa 188 PRT Artificial Sequence Consensus amino acid sequence 18 Ile Phe SerGlu Ser Tyr Gly Gly 1 5 19 14 PRT Artificial Sequence Consensus aminoacid sequence 19 Leu Ala Phe Tyr Trp Ile Leu Lys Ala Gly His Met Val Pro1 5 10 20 980 DNA Homo sapiens CDS (18)...(800) 20 cctgtggtcg ccccaggatg ctg aac cga atg gtg ggc ggg cag gac acg 50 Met Leu Asn Arg Met ValGly Gly Gln Asp Thr 1 5 10 cag gag ggc gag tgg ccc tgg caa gtc agc atccag cgc aac gga agc 98 Gln Glu Gly Glu Trp Pro Trp Gln Val Ser Ile GlnArg Asn Gly Ser 15 20 25 cac ttc tgc ggg ggc agc ctc atc gcg gag cag tgggtc ctg acg gct 146 His Phe Cys Gly Gly Ser Leu Ile Ala Glu Gln Trp ValLeu Thr Ala 30 35 40 gcg cac tgc ttc cgc aac acc tct gag acg tcc ctg taccag gtc ctg 194 Ala His Cys Phe Arg Asn Thr Ser Glu Thr Ser Leu Tyr GlnVal Leu 45 50 55 ctg ggg gca agg cag cta gtg cag ccg gga cca cac gct atgtat gcc 242 Leu Gly Ala Arg Gln Leu Val Gln Pro Gly Pro His Ala Met TyrAla 60 65 70 75 cgg gtg agg cag gtg gag agc aac ccc ctg tac cag ggc acggcc tcc 290 Arg Val Arg Gln Val Glu Ser Asn Pro Leu Tyr Gln Gly Thr AlaSer 80 85 90 agc gct gac gtg gcc ctg gtg gag ctg gag gca cca gtg ccc ttcacc 338 Ser Ala Asp Val Ala Leu Val Glu Leu Glu Ala Pro Val Pro Phe Thr95 100 105 aat tac atc ctc ccc gtg tgc ctg cct gac ccc tcg gtg atc tttgag 386 Asn Tyr Ile Leu Pro Val Cys Leu Pro Asp Pro Ser Val Ile Phe Glu110 115 120 acg ggc atg aac tgc tgg gtc act ggc tgg ggc agc ccc agt gaggaa 434 Thr Gly Met Asn Cys Trp Val Thr Gly Trp Gly Ser Pro Ser Glu Glu125 130 135 gac ctc ctg ccc gaa ccg cgg atc ctg cag aaa ctc gct gtg cccatc 482 Asp Leu Leu Pro Glu Pro Arg Ile Leu Gln Lys Leu Ala Val Pro Ile140 145 150 155 atc gac aca ccc aag tgc aac ctg ctc tac agc aaa gac accgag ttt 530 Ile Asp Thr Pro Lys Cys Asn Leu Leu Tyr Ser Lys Asp Thr GluPhe 160 165 170 ggc tac caa ccc aaa acc atc aag aat gac atg ctg tgc gccggc ttc 578 Gly Tyr Gln Pro Lys Thr Ile Lys Asn Asp Met Leu Cys Ala GlyPhe 175 180 185 gag gag ggc aag aag gat gcc tgc aag ggc gac tcg ggc ggcccc ctg 626 Glu Glu Gly Lys Lys Asp Ala Cys Lys Gly Asp Ser Gly Gly ProLeu 190 195 200 gtg tgc ctc gtg ggt cag tcg tgg ctg cag gcg ggg gtg atcagc tgg 674 Val Cys Leu Val Gly Gln Ser Trp Leu Gln Ala Gly Val Ile SerTrp 205 210 215 ggt gag ggc tgt gcc cgc cag aac cgc cca ggt gtc tac atccgt gtc 722 Gly Glu Gly Cys Ala Arg Gln Asn Arg Pro Gly Val Tyr Ile ArgVal 220 225 230 235 acc gcc cac cac aac tgg atc cat cgg atc atc ccc aaactg cag ttc 770 Thr Ala His His Asn Trp Ile His Arg Ile Ile Pro Lys LeuGln Phe 240 245 250 cag cca gcg agg ttg ggc ggc cag aag tga gacccccggggccaggagcc 820 Gln Pro Ala Arg Leu Gly Gly Gln Lys * 255 260 ccttgagcagagctctgcac ccagcctgcc cgcccacacc atcctgctgg tcctcccagc 880 gctgctgttgcacctgtgag ccccaccaga ctcatttgta aatagcgctc cttcctcccc 940 tctcaaatacccttatttta tttatgtttc tcccaataaa 980 21 260 PRT Homo sapiens 21 Met LeuAsn Arg Met Val Gly Gly Gln Asp Thr Gln Glu Gly Glu Trp 1 5 10 15 ProTrp Gln Val Ser Ile Gln Arg Asn Gly Ser His Phe Cys Gly Gly 20 25 30 SerLeu Ile Ala Glu Gln Trp Val Leu Thr Ala Ala His Cys Phe Arg 35 40 45 AsnThr Ser Glu Thr Ser Leu Tyr Gln Val Leu Leu Gly Ala Arg Gln 50 55 60 LeuVal Gln Pro Gly Pro His Ala Met Tyr Ala Arg Val Arg Gln Val 65 70 75 80Glu Ser Asn Pro Leu Tyr Gln Gly Thr Ala Ser Ser Ala Asp Val Ala 85 90 95Leu Val Glu Leu Glu Ala Pro Val Pro Phe Thr Asn Tyr Ile Leu Pro 100 105110 Val Cys Leu Pro Asp Pro Ser Val Ile Phe Glu Thr Gly Met Asn Cys 115120 125 Trp Val Thr Gly Trp Gly Ser Pro Ser Glu Glu Asp Leu Leu Pro Glu130 135 140 Pro Arg Ile Leu Gln Lys Leu Ala Val Pro Ile Ile Asp Thr ProLys 145 150 155 160 Cys Asn Leu Leu Tyr Ser Lys Asp Thr Glu Phe Gly TyrGln Pro Lys 165 170 175 Thr Ile Lys Asn Asp Met Leu Cys Ala Gly Phe GluGlu Gly Lys Lys 180 185 190 Asp Ala Cys Lys Gly Asp Ser Gly Gly Pro LeuVal Cys Leu Val Gly 195 200 205 Gln Ser Trp Leu Gln Ala Gly Val Ile SerTrp Gly Glu Gly Cys Ala 210 215 220 Arg Gln Asn Arg Pro Gly Val Tyr IleArg Val Thr Ala His His Asn 225 230 235 240 Trp Ile His Arg Ile Ile ProLys Leu Gln Phe Gln Pro Ala Arg Leu 245 250 255 Gly Gly Gln Lys 260 22783 DNA Homo sapiens CDS (1)...(783) 22 atg ctg aac cga atg gtg ggc gggcag gac acg cag gag ggc gag tgg 48 Met Leu Asn Arg Met Val Gly Gly GlnAsp Thr Gln Glu Gly Glu Trp 1 5 10 15 ccc tgg caa gtc agc atc cag cgcaac gga agc cac ttc tgc ggg ggc 96 Pro Trp Gln Val Ser Ile Gln Arg AsnGly Ser His Phe Cys Gly Gly 20 25 30 agc ctc atc gcg gag cag tgg gtc ctgacg gct gcg cac tgc ttc cgc 144 Ser Leu Ile Ala Glu Gln Trp Val Leu ThrAla Ala His Cys Phe Arg 35 40 45 aac acc tct gag acg tcc ctg tac cag gtcctg ctg ggg gca agg cag 192 Asn Thr Ser Glu Thr Ser Leu Tyr Gln Val LeuLeu Gly Ala Arg Gln 50 55 60 cta gtg cag ccg gga cca cac gct atg tat gcccgg gtg agg cag gtg 240 Leu Val Gln Pro Gly Pro His Ala Met Tyr Ala ArgVal Arg Gln Val 65 70 75 80 gag agc aac ccc ctg tac cag ggc acg gcc tccagc gct gac gtg gcc 288 Glu Ser Asn Pro Leu Tyr Gln Gly Thr Ala Ser SerAla Asp Val Ala 85 90 95 ctg gtg gag ctg gag gca cca gtg ccc ttc acc aattac atc ctc ccc 336 Leu Val Glu Leu Glu Ala Pro Val Pro Phe Thr Asn TyrIle Leu Pro 100 105 110 gtg tgc ctg cct gac ccc tcg gtg atc ttt gag acgggc atg aac tgc 384 Val Cys Leu Pro Asp Pro Ser Val Ile Phe Glu Thr GlyMet Asn Cys 115 120 125 tgg gtc act ggc tgg ggc agc ccc agt gag gaa gacctc ctg ccc gaa 432 Trp Val Thr Gly Trp Gly Ser Pro Ser Glu Glu Asp LeuLeu Pro Glu 130 135 140 ccg cgg atc ctg cag aaa ctc gct gtg ccc atc atcgac aca ccc aag 480 Pro Arg Ile Leu Gln Lys Leu Ala Val Pro Ile Ile AspThr Pro Lys 145 150 155 160 tgc aac ctg ctc tac agc aaa gac acc gag tttggc tac caa ccc aaa 528 Cys Asn Leu Leu Tyr Ser Lys Asp Thr Glu Phe GlyTyr Gln Pro Lys 165 170 175 acc atc aag aat gac atg ctg tgc gcc ggc ttcgag gag ggc aag aag 576 Thr Ile Lys Asn Asp Met Leu Cys Ala Gly Phe GluGlu Gly Lys Lys 180 185 190 gat gcc tgc aag ggc gac tcg ggc ggc ccc ctggtg tgc ctc gtg ggt 624 Asp Ala Cys Lys Gly Asp Ser Gly Gly Pro Leu ValCys Leu Val Gly 195 200 205 cag tcg tgg ctg cag gcg ggg gtg atc agc tggggt gag ggc tgt gcc 672 Gln Ser Trp Leu Gln Ala Gly Val Ile Ser Trp GlyGlu Gly Cys Ala 210 215 220 cgc cag aac cgc cca ggt gtc tac atc cgt gtcacc gcc cac cac aac 720 Arg Gln Asn Arg Pro Gly Val Tyr Ile Arg Val ThrAla His His Asn 225 230 235 240 tgg atc cat cgg atc atc ccc aaa ctg cagttc cag cca gcg agg ttg 768 Trp Ile His Arg Ile Ile Pro Lys Leu Gln PheGln Pro Ala Arg Leu 245 250 255 ggc ggc cag aag tga 783 Gly Gly GlnLys * 260 23 271 PRT Artificial Sequence Consensus amino acid sequenceof trypsin-like domain 23 Arg Ile Val Gly Gly Ser Glu Ala Lys Ile GlySer Phe Pro Trp Gln 1 5 10 15 Val Ser Leu Gln Xaa Xaa Xaa Xaa Xaa XaaCys Gly Gly Ser Leu Ile 20 25 30 Ser Pro Arg Trp Val Leu Thr Ala Ala HisCys Xaa Xaa Xaa Xaa Xaa 35 40 45 Xaa Xaa Xaa Xaa Xaa Arg Val Arg Leu GlySer His Asp Leu Ser Ser 50 55 60 Gly Glu Glu Thr Glu Gly Gly Pro Arg LeuAsp Ser Pro Gly Gly Gln 65 70 75 80 Val Ile Lys Val Ser Lys Ile Ile GluVal His Pro Asn Tyr Asn Xaa 85 90 95 Xaa Xaa Xaa Xaa Asn Asp Ile Ala LeuLeu Lys Leu Lys Glu Pro Val 100 105 110 Thr Leu Ser Asp Ser Asn Thr ValArg Pro Ile Cys Leu Pro Ser Ser 115 120 125 Asn Glu Ile Lys Thr Ser GluGly Asn Thr Val Pro Ala Gly Thr Thr 130 135 140 Cys Thr Val Ser Gly TrpGly Arg Thr Ser Glu Gly Pro Glu Glu Ser 145 150 155 160 Gly Gly Gly SerLeu Pro Asp Val Leu Gln Glu Val Asn Val Pro Ile 165 170 175 Val Ser AsnGlu Thr Cys Arg Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 180 185 190 Xaa XaaXaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Met Leu Cys Ala Gly Tyr 195 200 205 LeuGlu Gly Gly Asn Thr Pro Gly Gly Lys Asp Ala Cys Gln Gly Asp 210 215 220Gly Gly Pro Leu Val Cys Xaa Xaa Xaa Xaa Xaa Xaa Val Leu Val Gly 225 230235 240 Ile Val Ser Trp Gly Ser Ser Ser Leu Tyr Gly Cys Ala Arg Pro Asn245 250 255 Lys Pro Gly Val Tyr Thr Arg Val Ser Ser Tyr Leu Asp Trp Ile260 265 270 24 7 PRT Artificial Sequence Consensus amino acid sequence24 Gly Asp Ser Gly Gly Pro Leu 1 5 25 7220 DNA Homo sapiens CDS(129)...(2900) 25 agcggcgagc cgcgaaccag gcagtccggg gcatccagac tgcaggccgcgcccaggccg 60 cgcccaggct gcgccgcccg cctgcctccc gcgctgccgc gtcgccagtgctagcgctcc 120 tctccagc atg ctg cgg cgg ggc agc cag gcg ctc cgg cgc ttctcc act 170 Met Leu Arg Arg Gly Ser Gln Ala Leu Arg Arg Phe Ser Thr 1 510 ggc cgg gtt tat ttc aaa aac aag ctg aag ttg gca cta att ggc cag 218Gly Arg Val Tyr Phe Lys Asn Lys Leu Lys Leu Ala Leu Ile Gly Gln 15 20 2530 agc ctc ttt gga caa gaa gtc tat agc cac ctc cgc aaa gag ggc cac 266Ser Leu Phe Gly Gln Glu Val Tyr Ser His Leu Arg Lys Glu Gly His 35 40 45cga gta gta ggg gtg ttc aca gtt cca gac aag gat gga aaa gct gac 314 ArgVal Val Gly Val Phe Thr Val Pro Asp Lys Asp Gly Lys Ala Asp 50 55 60 cctctg gct ttg gct gca gag aaa gat ggg acc cct gtg ttc aag ctt 362 Pro LeuAla Leu Ala Ala Glu Lys Asp Gly Thr Pro Val Phe Lys Leu 65 70 75 cct aaatgg agg gtc aag ggc aag acc atc aaa gaa gtg gca gaa gcc 410 Pro Lys TrpArg Val Lys Gly Lys Thr Ile Lys Glu Val Ala Glu Ala 80 85 90 tac aga tccgtg ggt gca gag cta aat gtg ctc cct ttc tgc act cag 458 Tyr Arg Ser ValGly Ala Glu Leu Asn Val Leu Pro Phe Cys Thr Gln 95 100 105 110 ttc attccc atg gat ata att gat agt cca aag cac ggc tct atc att 506 Phe Ile ProMet Asp Ile Ile Asp Ser Pro Lys His Gly Ser Ile Ile 115 120 125 tat caccca tcc atc ctg ccc agg cac aga gga gcc tct gct atc aat 554 Tyr His ProSer Ile Leu Pro Arg His Arg Gly Ala Ser Ala Ile Asn 130 135 140 tgg actcta att atg gga gat aag aaa gct ggg ttt tct gtt ttc tgg 602 Trp Thr LeuIle Met Gly Asp Lys Lys Ala Gly Phe Ser Val Phe Trp 145 150 155 gct gatgat ggc ttg gat aca gga ccc atc ctt ctt cag aga tca tgt 650 Ala Asp AspGly Leu Asp Thr Gly Pro Ile Leu Leu Gln Arg Ser Cys 160 165 170 gat gttgaa ccc aat gat aca gtg gat gca ctt tat aat cgg ttt ctt 698 Asp Val GluPro Asn Asp Thr Val Asp Ala Leu Tyr Asn Arg Phe Leu 175 180 185 190 tttcct gaa gga atc aag gcc atg gta gaa gct gtc caa ctc ata gct 746 Phe ProGlu Gly Ile Lys Ala Met Val Glu Ala Val Gln Leu Ile Ala 195 200 205 gatgga aaa gct cct cgt ata ccc cag cca gaa gaa ggg gca aca tat 794 Asp GlyLys Ala Pro Arg Ile Pro Gln Pro Glu Glu Gly Ala Thr Tyr 210 215 220 gaaggt atc cag aaa aag gaa aat gct gag att tct tgg gac cag tct 842 Glu GlyIle Gln Lys Lys Glu Asn Ala Glu Ile Ser Trp Asp Gln Ser 225 230 235 gccgaa gtt tta cat aac tgg att cga ggt cat gat aaa gtc cct gga 890 Ala GluVal Leu His Asn Trp Ile Arg Gly His Asp Lys Val Pro Gly 240 245 250 gcttgg aca gag ata aat gga cag atg gtc act ttc tat ggc tcg aca 938 Ala TrpThr Glu Ile Asn Gly Gln Met Val Thr Phe Tyr Gly Ser Thr 255 260 265 270tta ctg aat agc tct gtg cct cct gga gaa cca ctg gaa att aaa ggt 986 LeuLeu Asn Ser Ser Val Pro Pro Gly Glu Pro Leu Glu Ile Lys Gly 275 280 285gcc aag aag cct ggt ctc gtt acc aaa aat gga ctt gtt ctt ttt ggt 1034 AlaLys Lys Pro Gly Leu Val Thr Lys Asn Gly Leu Val Leu Phe Gly 290 295 300aac gat gga aaa gca ctg acg gtg aga aat ctg cag ttt gaa gat gga 1082 AsnAsp Gly Lys Ala Leu Thr Val Arg Asn Leu Gln Phe Glu Asp Gly 305 310 315aaa atg atc cct gcc tct cag tac ttt tca acg ggt gag acg tca gtg 1130 LysMet Ile Pro Ala Ser Gln Tyr Phe Ser Thr Gly Glu Thr Ser Val 320 325 330gta gaa ctg aca gct gaa gag gtg aaa gtg gca gag acc atc aag gtc 1178 ValGlu Leu Thr Ala Glu Glu Val Lys Val Ala Glu Thr Ile Lys Val 335 340 345350 atc tgg gct gga att tta agc aat gtc ccc att att gaa gac tca aca 1226Ile Trp Ala Gly Ile Leu Ser Asn Val Pro Ile Ile Glu Asp Ser Thr 355 360365 gac ttc ttt aaa tct gga gca agc tca atg gat gtt gcc agg ctg gtt 1274Asp Phe Phe Lys Ser Gly Ala Ser Ser Met Asp Val Ala Arg Leu Val 370 375380 gaa gag atc aga cag aaa tgt ggt ggg ctt cag ttg cag aat gaa gat 1322Glu Glu Ile Arg Gln Lys Cys Gly Gly Leu Gln Leu Gln Asn Glu Asp 385 390395 gtc tat atg gcc acc aag ttt gaa ggc ttt atc caa aag gtc gtg agg 1370Val Tyr Met Ala Thr Lys Phe Glu Gly Phe Ile Gln Lys Val Val Arg 400 405410 aaa ctg aga gga gaa gat caa gag gtg gag ctg gtt gta gat tat att 1418Lys Leu Arg Gly Glu Asp Gln Glu Val Glu Leu Val Val Asp Tyr Ile 415 420425 430 tca aag gag gtc aat gaa atc atg gta aaa atg cca tac cag tgt ttc1466 Ser Lys Glu Val Asn Glu Ile Met Val Lys Met Pro Tyr Gln Cys Phe 435440 445 ata aat gga cag ttc aca gat gca gac gat gga aag act tac gac act1514 Ile Asn Gly Gln Phe Thr Asp Ala Asp Asp Gly Lys Thr Tyr Asp Thr 450455 460 atc aac cca aca gat gga tct aca ata tgc aaa gta tcc tac gct tct1562 Ile Asn Pro Thr Asp Gly Ser Thr Ile Cys Lys Val Ser Tyr Ala Ser 465470 475 ttg gcg gat gtt gat aaa gca gta gca gca gca aaa gat gct ttt gaa1610 Leu Ala Asp Val Asp Lys Ala Val Ala Ala Ala Lys Asp Ala Phe Glu 480485 490 aac ggt gaa tgg gga aga atg aat gca aga gaa aga gga aga ttg atg1658 Asn Gly Glu Trp Gly Arg Met Asn Ala Arg Glu Arg Gly Arg Leu Met 495500 505 510 tat aga ctt gca gac cta ctg gaa gag aac caa gaa gag ctg gcaact 1706 Tyr Arg Leu Ala Asp Leu Leu Glu Glu Asn Gln Glu Glu Leu Ala Thr515 520 525 att gaa gcc ctt gat tca ggg gct gtc tat acc ttg gcc ctg aagaca 1754 Ile Glu Ala Leu Asp Ser Gly Ala Val Tyr Thr Leu Ala Leu Lys Thr530 535 540 cac att gga atg tct gtg caa aca ttc aga tat ttt gct ggc tggtgc 1802 His Ile Gly Met Ser Val Gln Thr Phe Arg Tyr Phe Ala Gly Trp Cys545 550 555 gac aaa att cag ggt tct act att cca atc aac cag gcc cgt ccaaat 1850 Asp Lys Ile Gln Gly Ser Thr Ile Pro Ile Asn Gln Ala Arg Pro Asn560 565 570 cgc aat ctg acc ttc acc aag aaa gag cca ctc ggt gtc tgt gccatt 1898 Arg Asn Leu Thr Phe Thr Lys Lys Glu Pro Leu Gly Val Cys Ala Ile575 580 585 590 att att ccc tgg aac tac ccg ctg atg atg ctg gca tgg aagagt gct 1946 Ile Ile Pro Trp Asn Tyr Pro Leu Met Met Leu Ala Trp Lys SerAla 595 600 605 gcg tgt ttg gca gca ggc aat acc tta gtg ctc aag cca gcacag gtc 1994 Ala Cys Leu Ala Ala Gly Asn Thr Leu Val Leu Lys Pro Ala GlnVal 610 615 620 acg ccc ttg act gct ttg aag ttt gca gaa ctg tct gtg aaagca ggc 2042 Thr Pro Leu Thr Ala Leu Lys Phe Ala Glu Leu Ser Val Lys AlaGly 625 630 635 ttt cca aag ggg gtc atc aac atc att cca ggc tca ggt ggcata gca 2090 Phe Pro Lys Gly Val Ile Asn Ile Ile Pro Gly Ser Gly Gly IleAla 640 645 650 gga caa cgt ctg tct gaa cat cct gac atc cgc aaa ctt ggtttc act 2138 Gly Gln Arg Leu Ser Glu His Pro Asp Ile Arg Lys Leu Gly PheThr 655 660 665 670 gga tcc act cct att ggc aaa cag atc atg aag agc tgtgct gtt agc 2186 Gly Ser Thr Pro Ile Gly Lys Gln Ile Met Lys Ser Cys AlaVal Ser 675 680 685 aac ttg aag aaa gtt tcc ctt gag ctt ggt ggc aag tctcca ctt ata 2234 Asn Leu Lys Lys Val Ser Leu Glu Leu Gly Gly Lys Ser ProLeu Ile 690 695 700 ata ttt aat gac tgt gaa ctt gac aag gct gtg cga atgggc atg gga 2282 Ile Phe Asn Asp Cys Glu Leu Asp Lys Ala Val Arg Met GlyMet Gly 705 710 715 gca gta ttt ttc aac aaa gga gag aac tgt att gct gctggg cgg ttg 2330 Ala Val Phe Phe Asn Lys Gly Glu Asn Cys Ile Ala Ala GlyArg Leu 720 725 730 ttc gtg gaa gaa tcc atc cac gac gaa ttt gtg aca agagtg gta gaa 2378 Phe Val Glu Glu Ser Ile His Asp Glu Phe Val Thr Arg ValVal Glu 735 740 745 750 gaa att aaa aag atg aaa att ggt gat cca ctt gacaga tcc act gat 2426 Glu Ile Lys Lys Met Lys Ile Gly Asp Pro Leu Asp ArgSer Thr Asp 755 760 765 cat ggg ccc caa aat cat aag gct cat ctg gaa aagctg ctg caa tac 2474 His Gly Pro Gln Asn His Lys Ala His Leu Glu Lys LeuLeu Gln Tyr 770 775 780 tgt gaa act gga gtg aaa gaa ggg gcc act ttg gtgtac ggg gga aga 2522 Cys Glu Thr Gly Val Lys Glu Gly Ala Thr Leu Val TyrGly Gly Arg 785 790 795 caa gtc caa agg cca ggc ttt ttc atg gag ccg accgtg ttc aca gat 2570 Gln Val Gln Arg Pro Gly Phe Phe Met Glu Pro Thr ValPhe Thr Asp 800 805 810 gtg gaa gac tac atg tac ctc gcc aaa gag gaa tccttt ggg cct att 2618 Val Glu Asp Tyr Met Tyr Leu Ala Lys Glu Glu Ser PheGly Pro Ile 815 820 825 830 atg gtc att tct aaa ttc caa aat ggg gac atcgat gga gtg ttg cag 2666 Met Val Ile Ser Lys Phe Gln Asn Gly Asp Ile AspGly Val Leu Gln 835 840 845 cga gca aat agt aca gag tat ggt ttg gcc tcaggg gtt ttt aca aga 2714 Arg Ala Asn Ser Thr Glu Tyr Gly Leu Ala Ser GlyVal Phe Thr Arg 850 855 860 gac ata aac aaa gct atg tat gtg agt gaa aaactg gaa gca gga act 2762 Asp Ile Asn Lys Ala Met Tyr Val Ser Glu Lys LeuGlu Ala Gly Thr 865 870 875 gtt ttt att aac aca tac aac aag aca gat gtggcg gcc cca ttt ggc 2810 Val Phe Ile Asn Thr Tyr Asn Lys Thr Asp Val AlaAla Pro Phe Gly 880 885 890 gga gtt aaa caa tct ggc ttt gga aaa gac ttaggt gag gaa gct cta 2858 Gly Val Lys Gln Ser Gly Phe Gly Lys Asp Leu GlyGlu Glu Ala Leu 895 900 905 910 aat gaa tat ctc aaa acc aag acg gtg acactg gaa tat tag 2900 Asn Glu Tyr Leu Lys Thr Lys Thr Val Thr Leu GluTyr * 915 920 agcaacacca tcatcaggaa agccttgaca gacagccctt tacaactctggacacactta 2960 agaagattgg gtgtgttgag gcaggaggtg tcagccacaa accaaaaaatacacagatgg 3020 accatgaaga gggccaggcc atgttaaagc atttacacat gtgcctgagtattttctaat 3080 acaccttcca gtgatttgga gttgttgcat tttgactatg ttgtatatcatacgtatttc 3140 taaaatacca agctgtttct cccctaccta gacaaatcta ttcatggttcccatcttgaa 3200 gatgtcagta ccatgcagtt ataatacaca aggtgcattt attggaaactttgtataata 3260 tgtacaggtt tttaacctct gaactataca tagggggtta ttaaaaagattttctataag 3320 tcttctaagg aacagtataa cctgtaagga atgtgaaggt agttcttttttagtatttgg 3380 aaataagata catctttgtg cctttgatat tccatttttt aacccactgtgatgggtgat 3440 caacctagaa acattatctt gagtacctac taggtaccag gtactatattatgttctgag 3500 gagtatagag aatttaatga tatgatggct ggcccccaca tagtttaaattttagtaaat 3560 agcttttgaa gcaaatttta catatgatat agtagaaggc tgatccctggtcgtatcata 3620 ccatcttcct atctatgtaa ctttgggaaa ctctcgcaac tcctctgagcctctgcttcc 3680 ctatgtgtaa aacagggata gtaaatgcct tcctcaggac ccttaataggagaattcatt 3740 gcagtaatgt aagtaaagca cctcacatta atgctttgct catggtaagtactcaaattt 3800 aactctgatt tcctccgtca ccattcttaa aagatattga gatagtttaattaactagat 3860 gaattcattt cccacaaccc ttttcaatca tcaattccta gatatttttctcatccattg 3920 ttctgacaca atgcctgata cagcagcact gaaaaatgcc acacaatgaaaaatggcaat 3980 agtacaagga aaaggggtgc ttttctttgg gcagctcgct cgtccttcatgggacatctt 4040 actttccatt tttctaccta ttggttctgc tgttcactgg ctgtgtgatcttgggcaaga 4100 tagtaatcta atatctcaga gcctaggttg agtatctata aaatgaaaatcaaatctcta 4160 tctcagtagg tgttgcaagg attcagtgag ataatataca taatgcacttaacaaggcgt 4220 ttggaccata gcattgaaga aatggaaact attaacagcc catttcccattggcagacag 4280 aagtagtcag gtgagtaaat tttcaccatc tatgtgtgac tagaaggcggcaaatttctg 4340 aatcacatga gtctccaaaa gatagccaga aagttaaatt ctattaatcctcctttaaaa 4400 ataaaatttc agtaaacatt cctttttctt tggctttgaa gaagccttagggaatatttg 4460 tcattttgga gacttggcag aataacatga ggggattgta gggaatcaataaaaactaaa 4520 caacaaaatc agagtcagag aacattttca aaaggaagaa taggaggtttgatcccagca 4580 tgataaacag agcgaatttg gcctggaagc acttttgatt atactatagctcatttacca 4640 tcccagagtt tggcacagct gaaattttaa gttggaatga atattcactgggcccaaaat 4700 gacagttcat atttgaataa aagtgacaaa agccttttta taagtaatcacttttaagtg 4760 aaatgtttta actgatttca tgtgatttag aatatgattt aatcaaattattttaatgat 4820 agatggaatg gcagacaaaa acatgcctgt ccttctagac tgattttactttaccctcta 4880 atattcatct cagtagcagt gttttaaata ttctctgggc tgcaaaactctttgggaatc 4940 tgataaaagc tatgaacact ccctgtgtcc cgcttctacc cccaaaattcatgtgcacac 5000 acacaattct gcaagtatct tcaaagggtt cacagacctc ccaaaggccatgcttgggcc 5060 ccagattaag aactcctttc tccatagcaa gttttaaaca tttcttaccagcttacattt 5120 ttagatctgg ctgatcagaa tcaaaggctc tgtgtaatac ataaagttaccaagtgaact 5180 ggaattggaa catcaccctc cccagcctgc taggtgattt acttaacacatagagtaata 5240 aaatcatcgc tgttgcttta gatcacggat tattttgcta ataatgctaaggatgaagct 5300 gtgatcttat tatcacctga atcgggaggt gtggacactt taagcagttccactttcctt 5360 ctaattcccc atccccatgc ctttgctaaa gctgtccctt ttgctctaacacccttcctg 5420 gaccttccta ccctagctgg gctaagtgtt tctcctcagc gttcccacttgtttcaaaca 5480 tagcacttac cacttgtact aaaattactt gccttcttaa ttagatatgaacaaccctcc 5540 ccaactccag tatgggcctt ctgtcaataa taatacgata tgacagctaccatttattaa 5600 gggcctcctg tatgaaagac cttaggctaa gcatgtttta aatgttatttaatcttcaca 5660 atctctgaaa aaaatgaaga aatcaacgtg cttttcttac tacctctacccctaagccat 5720 tattactttt tttttttttt tgagacagag ttttgctctt gttgcccaggctgcagtgca 5780 gtggtgcaat cttggctcac tgcaacctct gcctcttggg ttcaagcgattgtcatgcct 5840 tagccttcca agtagctggg attacaggtg tgtgccacta cacctggctaagtagagatg 5900 gggtttcgcc atgttggcca ggctggtctt gaactcctga cctcaagtgatccacctgcc 5960 tccgcctccc aaagtgctgg gattacaggc atgaaccact gcacctggcctgttacctct 6020 ttcctacaat tttgctcaag tctcccaact ggtcttctgg attcctctcttctgcggtcc 6080 tgttcaaagc ttaagtcaga cagtgtcact tcactcgtct gtttaaaacctttcaatggc 6140 ccccatttca cgtagaccaa agtccaacgt atttacctgg cctactgatcttgctcctag 6200 ctacctctga cctcatctcc tgtcaatttc cctctcattc tgttccaccatcctgactgc 6260 cttgacttcc tcaacagaac aagcctgctc ctgcctcagg gcctctgtccttattcttcc 6320 tcttcccagg ggtgtgctgg taaaatattt aacaaatagt tctccgggacgggggagaaa 6380 accctcattt gtagcatttg caggtatcta tgtgtaaata ctctcatcaaggctattttt 6440 gagccactaa tttgccttca ctgaatacag agtttgggaa gagatgcatgccatcagaac 6500 aaatgcaagc cagcaccagc acaccactgc ctcttcctgc aactcttgtccatacacaac 6560 ctcatggctg gctggctcac ttcctgcagg tctctcctca aatatcatctgatgagagac 6620 acattccctg actatgcttt ctaaaatagg ccatatgccc ccacattcataccccatctg 6680 ctgtcattct ttattctttt tataagtgca ttattttcat agcacttatcactacctgtt 6740 gtatattaat caatgatctt ttcccattag aatgtaagtt tcatgaacaggtacttgttt 6800 taatactgta tctccagtcc taatgtgtaa caggagccca ataaatgtttgctttcaaat 6860 ggagaggtta agtaacctgc tcaaatcaca cagctattaa gtggcagaacaggttttcaa 6920 gcaatgcatc tggtggtttt aactaagtcg agatagtttt tattcctaatgcctaaatca 6980 gggcctaggt agtgagctgt gggcacatat taagtattgg ttaaactaaaaataataagc 7040 aaaatggaca ttatctataa aagcttttgt ggaaatggct agagctagggtaaggaaaca 7100 aatttggttc cccatacctg cccttcaaga aaataaagct gtcaaggaaaattgggctaa 7160 gagtaggata tgagggatga tggataaggc atgagacatg agaaaataagggggattaaa 7220 26 923 PRT Homo sapiens 26 Met Leu Arg Arg Gly Ser GlnAla Leu Arg Arg Phe Ser Thr Gly Arg 1 5 10 15 Val Tyr Phe Lys Asn LysLeu Lys Leu Ala Leu Ile Gly Gln Ser Leu 20 25 30 Phe Gly Gln Glu Val TyrSer His Leu Arg Lys Glu Gly His Arg Val 35 40 45 Val Gly Val Phe Thr ValPro Asp Lys Asp Gly Lys Ala Asp Pro Leu 50 55 60 Ala Leu Ala Ala Glu LysAsp Gly Thr Pro Val Phe Lys Leu Pro Lys 65 70 75 80 Trp Arg Val Lys GlyLys Thr Ile Lys Glu Val Ala Glu Ala Tyr Arg 85 90 95 Ser Val Gly Ala GluLeu Asn Val Leu Pro Phe Cys Thr Gln Phe Ile 100 105 110 Pro Met Asp IleIle Asp Ser Pro Lys His Gly Ser Ile Ile Tyr His 115 120 125 Pro Ser IleLeu Pro Arg His Arg Gly Ala Ser Ala Ile Asn Trp Thr 130 135 140 Leu IleMet Gly Asp Lys Lys Ala Gly Phe Ser Val Phe Trp Ala Asp 145 150 155 160Asp Gly Leu Asp Thr Gly Pro Ile Leu Leu Gln Arg Ser Cys Asp Val 165 170175 Glu Pro Asn Asp Thr Val Asp Ala Leu Tyr Asn Arg Phe Leu Phe Pro 180185 190 Glu Gly Ile Lys Ala Met Val Glu Ala Val Gln Leu Ile Ala Asp Gly195 200 205 Lys Ala Pro Arg Ile Pro Gln Pro Glu Glu Gly Ala Thr Tyr GluGly 210 215 220 Ile Gln Lys Lys Glu Asn Ala Glu Ile Ser Trp Asp Gln SerAla Glu 225 230 235 240 Val Leu His Asn Trp Ile Arg Gly His Asp Lys ValPro Gly Ala Trp 245 250 255 Thr Glu Ile Asn Gly Gln Met Val Thr Phe TyrGly Ser Thr Leu Leu 260 265 270 Asn Ser Ser Val Pro Pro Gly Glu Pro LeuGlu Ile Lys Gly Ala Lys 275 280 285 Lys Pro Gly Leu Val Thr Lys Asn GlyLeu Val Leu Phe Gly Asn Asp 290 295 300 Gly Lys Ala Leu Thr Val Arg AsnLeu Gln Phe Glu Asp Gly Lys Met 305 310 315 320 Ile Pro Ala Ser Gln TyrPhe Ser Thr Gly Glu Thr Ser Val Val Glu 325 330 335 Leu Thr Ala Glu GluVal Lys Val Ala Glu Thr Ile Lys Val Ile Trp 340 345 350 Ala Gly Ile LeuSer Asn Val Pro Ile Ile Glu Asp Ser Thr Asp Phe 355 360 365 Phe Lys SerGly Ala Ser Ser Met Asp Val Ala Arg Leu Val Glu Glu 370 375 380 Ile ArgGln Lys Cys Gly Gly Leu Gln Leu Gln Asn Glu Asp Val Tyr 385 390 395 400Met Ala Thr Lys Phe Glu Gly Phe Ile Gln Lys Val Val Arg Lys Leu 405 410415 Arg Gly Glu Asp Gln Glu Val Glu Leu Val Val Asp Tyr Ile Ser Lys 420425 430 Glu Val Asn Glu Ile Met Val Lys Met Pro Tyr Gln Cys Phe Ile Asn435 440 445 Gly Gln Phe Thr Asp Ala Asp Asp Gly Lys Thr Tyr Asp Thr IleAsn 450 455 460 Pro Thr Asp Gly Ser Thr Ile Cys Lys Val Ser Tyr Ala SerLeu Ala 465 470 475 480 Asp Val Asp Lys Ala Val Ala Ala Ala Lys Asp AlaPhe Glu Asn Gly 485 490 495 Glu Trp Gly Arg Met Asn Ala Arg Glu Arg GlyArg Leu Met Tyr Arg 500 505 510 Leu Ala Asp Leu Leu Glu Glu Asn Gln GluGlu Leu Ala Thr Ile Glu 515 520 525 Ala Leu Asp Ser Gly Ala Val Tyr ThrLeu Ala Leu Lys Thr His Ile 530 535 540 Gly Met Ser Val Gln Thr Phe ArgTyr Phe Ala Gly Trp Cys Asp Lys 545 550 555 560 Ile Gln Gly Ser Thr IlePro Ile Asn Gln Ala Arg Pro Asn Arg Asn 565 570 575 Leu Thr Phe Thr LysLys Glu Pro Leu Gly Val Cys Ala Ile Ile Ile 580 585 590 Pro Trp Asn TyrPro Leu Met Met Leu Ala Trp Lys Ser Ala Ala Cys 595 600 605 Leu Ala AlaGly Asn Thr Leu Val Leu Lys Pro Ala Gln Val Thr Pro 610 615 620 Leu ThrAla Leu Lys Phe Ala Glu Leu Ser Val Lys Ala Gly Phe Pro 625 630 635 640Lys Gly Val Ile Asn Ile Ile Pro Gly Ser Gly Gly Ile Ala Gly Gln 645 650655 Arg Leu Ser Glu His Pro Asp Ile Arg Lys Leu Gly Phe Thr Gly Ser 660665 670 Thr Pro Ile Gly Lys Gln Ile Met Lys Ser Cys Ala Val Ser Asn Leu675 680 685 Lys Lys Val Ser Leu Glu Leu Gly Gly Lys Ser Pro Leu Ile IlePhe 690 695 700 Asn Asp Cys Glu Leu Asp Lys Ala Val Arg Met Gly Met GlyAla Val 705 710 715 720 Phe Phe Asn Lys Gly Glu Asn Cys Ile Ala Ala GlyArg Leu Phe Val 725 730 735 Glu Glu Ser Ile His Asp Glu Phe Val Thr ArgVal Val Glu Glu Ile 740 745 750 Lys Lys Met Lys Ile Gly Asp Pro Leu AspArg Ser Thr Asp His Gly 755 760 765 Pro Gln Asn His Lys Ala His Leu GluLys Leu Leu Gln Tyr Cys Glu 770 775 780 Thr Gly Val Lys Glu Gly Ala ThrLeu Val Tyr Gly Gly Arg Gln Val 785 790 795 800 Gln Arg Pro Gly Phe PheMet Glu Pro Thr Val Phe Thr Asp Val Glu 805 810 815 Asp Tyr Met Tyr LeuAla Lys Glu Glu Ser Phe Gly Pro Ile Met Val 820 825 830 Ile Ser Lys PheGln Asn Gly Asp Ile Asp Gly Val Leu Gln Arg Ala 835 840 845 Asn Ser ThrGlu Tyr Gly Leu Ala Ser Gly Val Phe Thr Arg Asp Ile 850 855 860 Asn LysAla Met Tyr Val Ser Glu Lys Leu Glu Ala Gly Thr Val Phe 865 870 875 880Ile Asn Thr Tyr Asn Lys Thr Asp Val Ala Ala Pro Phe Gly Gly Val 885 890895 Lys Gln Ser Gly Phe Gly Lys Asp Leu Gly Glu Glu Ala Leu Asn Glu 900905 910 Tyr Leu Lys Thr Lys Thr Val Thr Leu Glu Tyr 915 920 27 2772 DNAHomo sapiens CDS (1)...(2772) 27 atg ctg cgg cgg ggc agc cag gcg ctc cggcgc ttc tcc act ggc cgg 48 Met Leu Arg Arg Gly Ser Gln Ala Leu Arg ArgPhe Ser Thr Gly Arg 1 5 10 15 gtt tat ttc aaa aac aag ctg aag ttg gcacta att ggc cag agc ctc 96 Val Tyr Phe Lys Asn Lys Leu Lys Leu Ala LeuIle Gly Gln Ser Leu 20 25 30 ttt gga caa gaa gtc tat agc cac ctc cgc aaagag ggc cac cga gta 144 Phe Gly Gln Glu Val Tyr Ser His Leu Arg Lys GluGly His Arg Val 35 40 45 gta ggg gtg ttc aca gtt cca gac aag gat gga aaagct gac cct ctg 192 Val Gly Val Phe Thr Val Pro Asp Lys Asp Gly Lys AlaAsp Pro Leu 50 55 60 gct ttg gct gca gag aaa gat ggg acc cct gtg ttc aagctt cct aaa 240 Ala Leu Ala Ala Glu Lys Asp Gly Thr Pro Val Phe Lys LeuPro Lys 65 70 75 80 tgg agg gtc aag ggc aag acc atc aaa gaa gtg gca gaagcc tac aga 288 Trp Arg Val Lys Gly Lys Thr Ile Lys Glu Val Ala Glu AlaTyr Arg 85 90 95 tcc gtg ggt gca gag cta aat gtg ctc cct ttc tgc act cagttc att 336 Ser Val Gly Ala Glu Leu Asn Val Leu Pro Phe Cys Thr Gln PheIle 100 105 110 ccc atg gat ata att gat agt cca aag cac ggc tct atc atttat cac 384 Pro Met Asp Ile Ile Asp Ser Pro Lys His Gly Ser Ile Ile TyrHis 115 120 125 cca tcc atc ctg ccc agg cac aga gga gcc tct gct atc aattgg act 432 Pro Ser Ile Leu Pro Arg His Arg Gly Ala Ser Ala Ile Asn TrpThr 130 135 140 cta att atg gga gat aag aaa gct ggg ttt tct gtt ttc tgggct gat 480 Leu Ile Met Gly Asp Lys Lys Ala Gly Phe Ser Val Phe Trp AlaAsp 145 150 155 160 gat ggc ttg gat aca gga ccc atc ctt ctt cag aga tcatgt gat gtt 528 Asp Gly Leu Asp Thr Gly Pro Ile Leu Leu Gln Arg Ser CysAsp Val 165 170 175 gaa ccc aat gat aca gtg gat gca ctt tat aat cgg tttctt ttt cct 576 Glu Pro Asn Asp Thr Val Asp Ala Leu Tyr Asn Arg Phe LeuPhe Pro 180 185 190 gaa gga atc aag gcc atg gta gaa gct gtc caa ctc atagct gat gga 624 Glu Gly Ile Lys Ala Met Val Glu Ala Val Gln Leu Ile AlaAsp Gly 195 200 205 aaa gct cct cgt ata ccc cag cca gaa gaa ggg gca acatat gaa ggt 672 Lys Ala Pro Arg Ile Pro Gln Pro Glu Glu Gly Ala Thr TyrGlu Gly 210 215 220 atc cag aaa aag gaa aat gct gag att tct tgg gac cagtct gcc gaa 720 Ile Gln Lys Lys Glu Asn Ala Glu Ile Ser Trp Asp Gln SerAla Glu 225 230 235 240 gtt tta cat aac tgg att cga ggt cat gat aaa gtccct gga gct tgg 768 Val Leu His Asn Trp Ile Arg Gly His Asp Lys Val ProGly Ala Trp 245 250 255 aca gag ata aat gga cag atg gtc act ttc tat ggctcg aca tta ctg 816 Thr Glu Ile Asn Gly Gln Met Val Thr Phe Tyr Gly SerThr Leu Leu 260 265 270 aat agc tct gtg cct cct gga gaa cca ctg gaa attaaa ggt gcc aag 864 Asn Ser Ser Val Pro Pro Gly Glu Pro Leu Glu Ile LysGly Ala Lys 275 280 285 aag cct ggt ctc gtt acc aaa aat gga ctt gtt cttttt ggt aac gat 912 Lys Pro Gly Leu Val Thr Lys Asn Gly Leu Val Leu PheGly Asn Asp 290 295 300 gga aaa gca ctg acg gtg aga aat ctg cag ttt gaagat gga aaa atg 960 Gly Lys Ala Leu Thr Val Arg Asn Leu Gln Phe Glu AspGly Lys Met 305 310 315 320 atc cct gcc tct cag tac ttt tca acg ggt gagacg tca gtg gta gaa 1008 Ile Pro Ala Ser Gln Tyr Phe Ser Thr Gly Glu ThrSer Val Val Glu 325 330 335 ctg aca gct gaa gag gtg aaa gtg gca gag accatc aag gtc atc tgg 1056 Leu Thr Ala Glu Glu Val Lys Val Ala Glu Thr IleLys Val Ile Trp 340 345 350 gct gga att tta agc aat gtc ccc att att gaagac tca aca gac ttc 1104 Ala Gly Ile Leu Ser Asn Val Pro Ile Ile Glu AspSer Thr Asp Phe 355 360 365 ttt aaa tct gga gca agc tca atg gat gtt gccagg ctg gtt gaa gag 1152 Phe Lys Ser Gly Ala Ser Ser Met Asp Val Ala ArgLeu Val Glu Glu 370 375 380 atc aga cag aaa tgt ggt ggg ctt cag ttg cagaat gaa gat gtc tat 1200 Ile Arg Gln Lys Cys Gly Gly Leu Gln Leu Gln AsnGlu Asp Val Tyr 385 390 395 400 atg gcc acc aag ttt gaa ggc ttt atc caaaag gtc gtg agg aaa ctg 1248 Met Ala Thr Lys Phe Glu Gly Phe Ile Gln LysVal Val Arg Lys Leu 405 410 415 aga gga gaa gat caa gag gtg gag ctg gttgta gat tat att tca aag 1296 Arg Gly Glu Asp Gln Glu Val Glu Leu Val ValAsp Tyr Ile Ser Lys 420 425 430 gag gtc aat gaa atc atg gta aaa atg ccatac cag tgt ttc ata aat 1344 Glu Val Asn Glu Ile Met Val Lys Met Pro TyrGln Cys Phe Ile Asn 435 440 445 gga cag ttc aca gat gca gac gat gga aagact tac gac act atc aac 1392 Gly Gln Phe Thr Asp Ala Asp Asp Gly Lys ThrTyr Asp Thr Ile Asn 450 455 460 cca aca gat gga tct aca ata tgc aaa gtatcc tac gct tct ttg gcg 1440 Pro Thr Asp Gly Ser Thr Ile Cys Lys Val SerTyr Ala Ser Leu Ala 465 470 475 480 gat gtt gat aaa gca gta gca gca gcaaaa gat gct ttt gaa aac ggt 1488 Asp Val Asp Lys Ala Val Ala Ala Ala LysAsp Ala Phe Glu Asn Gly 485 490 495 gaa tgg gga aga atg aat gca aga gaaaga gga aga ttg atg tat aga 1536 Glu Trp Gly Arg Met Asn Ala Arg Glu ArgGly Arg Leu Met Tyr Arg 500 505 510 ctt gca gac cta ctg gaa gag aac caagaa gag ctg gca act att gaa 1584 Leu Ala Asp Leu Leu Glu Glu Asn Gln GluGlu Leu Ala Thr Ile Glu 515 520 525 gcc ctt gat tca ggg gct gtc tat accttg gcc ctg aag aca cac att 1632 Ala Leu Asp Ser Gly Ala Val Tyr Thr LeuAla Leu Lys Thr His Ile 530 535 540 gga atg tct gtg caa aca ttc aga tatttt gct ggc tgg tgc gac aaa 1680 Gly Met Ser Val Gln Thr Phe Arg Tyr PheAla Gly Trp Cys Asp Lys 545 550 555 560 att cag ggt tct act att cca atcaac cag gcc cgt cca aat cgc aat 1728 Ile Gln Gly Ser Thr Ile Pro Ile AsnGln Ala Arg Pro Asn Arg Asn 565 570 575 ctg acc ttc acc aag aaa gag ccactc ggt gtc tgt gcc att att att 1776 Leu Thr Phe Thr Lys Lys Glu Pro LeuGly Val Cys Ala Ile Ile Ile 580 585 590 ccc tgg aac tac ccg ctg atg atgctg gca tgg aag agt gct gcg tgt 1824 Pro Trp Asn Tyr Pro Leu Met Met LeuAla Trp Lys Ser Ala Ala Cys 595 600 605 ttg gca gca ggc aat acc tta gtgctc aag cca gca cag gtc acg ccc 1872 Leu Ala Ala Gly Asn Thr Leu Val LeuLys Pro Ala Gln Val Thr Pro 610 615 620 ttg act gct ttg aag ttt gca gaactg tct gtg aaa gca ggc ttt cca 1920 Leu Thr Ala Leu Lys Phe Ala Glu LeuSer Val Lys Ala Gly Phe Pro 625 630 635 640 aag ggg gtc atc aac atc attcca ggc tca ggt ggc ata gca gga caa 1968 Lys Gly Val Ile Asn Ile Ile ProGly Ser Gly Gly Ile Ala Gly Gln 645 650 655 cgt ctg tct gaa cat cct gacatc cgc aaa ctt ggt ttc act gga tcc 2016 Arg Leu Ser Glu His Pro Asp IleArg Lys Leu Gly Phe Thr Gly Ser 660 665 670 act cct att ggc aaa cag atcatg aag agc tgt gct gtt agc aac ttg 2064 Thr Pro Ile Gly Lys Gln Ile MetLys Ser Cys Ala Val Ser Asn Leu 675 680 685 aag aaa gtt tcc ctt gag cttggt ggc aag tct cca ctt ata ata ttt 2112 Lys Lys Val Ser Leu Glu Leu GlyGly Lys Ser Pro Leu Ile Ile Phe 690 695 700 aat gac tgt gaa ctt gac aaggct gtg cga atg ggc atg gga gca gta 2160 Asn Asp Cys Glu Leu Asp Lys AlaVal Arg Met Gly Met Gly Ala Val 705 710 715 720 ttt ttc aac aaa gga gagaac tgt att gct gct ggg cgg ttg ttc gtg 2208 Phe Phe Asn Lys Gly Glu AsnCys Ile Ala Ala Gly Arg Leu Phe Val 725 730 735 gaa gaa tcc atc cac gacgaa ttt gtg aca aga gtg gta gaa gaa att 2256 Glu Glu Ser Ile His Asp GluPhe Val Thr Arg Val Val Glu Glu Ile 740 745 750 aaa aag atg aaa att ggtgat cca ctt gac aga tcc act gat cat ggg 2304 Lys Lys Met Lys Ile Gly AspPro Leu Asp Arg Ser Thr Asp His Gly 755 760 765 ccc caa aat cat aag gctcat ctg gaa aag ctg ctg caa tac tgt gaa 2352 Pro Gln Asn His Lys Ala HisLeu Glu Lys Leu Leu Gln Tyr Cys Glu 770 775 780 act gga gtg aaa gaa ggggcc act ttg gtg tac ggg gga aga caa gtc 2400 Thr Gly Val Lys Glu Gly AlaThr Leu Val Tyr Gly Gly Arg Gln Val 785 790 795 800 caa agg cca ggc tttttc atg gag ccg acc gtg ttc aca gat gtg gaa 2448 Gln Arg Pro Gly Phe PheMet Glu Pro Thr Val Phe Thr Asp Val Glu 805 810 815 gac tac atg tac ctcgcc aaa gag gaa tcc ttt ggg cct att atg gtc 2496 Asp Tyr Met Tyr Leu AlaLys Glu Glu Ser Phe Gly Pro Ile Met Val 820 825 830 att tct aaa ttc caaaat ggg gac atc gat gga gtg ttg cag cga gca 2544 Ile Ser Lys Phe Gln AsnGly Asp Ile Asp Gly Val Leu Gln Arg Ala 835 840 845 aat agt aca gag tatggt ttg gcc tca ggg gtt ttt aca aga gac ata 2592 Asn Ser Thr Glu Tyr GlyLeu Ala Ser Gly Val Phe Thr Arg Asp Ile 850 855 860 aac aaa gct atg tatgtg agt gaa aaa ctg gaa gca gga act gtt ttt 2640 Asn Lys Ala Met Tyr ValSer Glu Lys Leu Glu Ala Gly Thr Val Phe 865 870 875 880 att aac aca tacaac aag aca gat gtg gcg gcc cca ttt ggc gga gtt 2688 Ile Asn Thr Tyr AsnLys Thr Asp Val Ala Ala Pro Phe Gly Gly Val 885 890 895 aaa caa tct ggcttt gga aaa gac tta ggt gag gaa gct cta aat gaa 2736 Lys Gln Ser Gly PheGly Lys Asp Leu Gly Glu Glu Ala Leu Asn Glu 900 905 910 tat ctc aaa accaag acg gtg aca ctg gaa tat tag 2772 Tyr Leu Lys Thr Lys Thr Val Thr LeuGlu Tyr * 915 920 28 492 PRT Artificial Sequence Aldehyde dehydrogenasePfam consensus sequence 28 Glu Trp Val Asp Ser Ala Ser Gly Lys Thr PheGlu Val Val Asn Pro 1 5 10 15 Ala Asn Lys Gly Glu Val Ile Gly Arg ValPro Glu Ala Thr Ala Glu 20 25 30 Asp Val Asp Ala Ala Val Lys Ala Ala LysGlu Ala Phe Lys Ser Gly 35 40 45 Pro Trp Trp Ala Lys Val Pro Ala Ser GluArg Ala Arg Ile Leu Arg 50 55 60 Lys Leu Ala Asp Leu Ile Glu Glu Arg GluAsp Glu Leu Ala Ala Leu 65 70 75 80 Glu Thr Leu Asp Leu Gly Lys Pro LeuAla Glu Ala Lys Gly Asp Thr 85 90 95 Glu Val Gly Arg Ala Ile Asp Glu IleArg Tyr Tyr Ala Gly Trp Ala 100 105 110 Arg Lys Leu Met Gly Glu Arg ArgVal Ile Pro Ser Leu Ala Thr Asp 115 120 125 Gly Asp Glu Glu Leu Asn TyrThr Arg Arg Glu Pro Leu Gly Val Val 130 135 140 Gly Val Ile Ser Pro TrpAsn Phe Pro Leu Leu Leu Ala Leu Trp Lys 145 150 155 160 Leu Ala Pro AlaLeu Ala Ala Gly Asn Thr Val Val Leu Lys Pro Ser 165 170 175 Glu Gln ThrPro Leu Thr Ala Leu Leu Leu Ala Glu Leu Ile Glu Glu 180 185 190 Ala GlyAla Asn Asn Leu Pro Lys Gly Val Val Asn Val Val Pro Gly 195 200 205 PheGly Ala Glu Val Gly Gln Ala Leu Leu Ser His Pro Asp Ile Asp 210 215 220Lys Ile Ser Phe Thr Gly Ser Thr Glu Val Gly Lys Leu Ile Met Glu 225 230235 240 Ala Ala Ala Ala Lys Asn Leu Lys Lys Val Thr Leu Glu Leu Gly Gly245 250 255 Lys Ser Pro Val Ile Val Phe Asp Asp Ala Asp Leu Asp Lys AlaVal 260 265 270 Glu Arg Ile Val Phe Gly Ala Phe Gly Asn Ala Gly Gln ValCys Ile 275 280 285 Ala Pro Ser Arg Leu Leu Val His Glu Ser Ile Tyr AspGlu Phe Val 290 295 300 Glu Lys Leu Lys Glu Arg Val Lys Lys Leu Lys LeuIle Gly Asp Pro 305 310 315 320 Leu Asp Ser Asp Thr Asn Ile Tyr Gly ProLeu Ile Ser Glu Gln Gln 325 330 335 Phe Asp Arg Val Leu Ser Tyr Ile GluAsp Gly Lys Glu Glu Gly Ala 340 345 350 Lys Val Leu Cys Gly Gly Glu ArgAsp Glu Ser Lys Glu Tyr Leu Gly 355 360 365 Gly Gly Tyr Tyr Val Gln ProThr Ile Phe Thr Asp Val Thr Pro Asp 370 375 380 Met Lys Ile Met Lys GluGlu Ile Phe Gly Pro Val Leu Pro Ile Ile 385 390 395 400 Lys Phe Lys AspLeu Asp Glu Ala Ile Glu Leu Ala Asn Asp Thr Glu 405 410 415 Tyr Gly LeuAla Ala Tyr Val Phe Thr Lys Asp Ile Leu Ala Arg Ala 420 425 430 Phe ArgVal Ala Lys Ala Leu Glu Ala Gly Ile Val Trp Val Asn Asp 435 440 445 ValCys Val His Ala Ala Glu Pro Gln Leu Pro Phe Gly Gly Val Lys 450 455 460Gln Ser Ser Gly Ile Gly Arg Glu His Gly Gly Lys Tyr Gly Leu Glu 465 470475 480 Glu Tyr Thr Glu Ile Lys Thr Val Thr Ile Arg Leu 485 490 29 3513DNA Homo sapiens CDS (82)...(3150) 29 cgcacccagt caccagcgtt cgggagcctgtcgcagcggg accgacggaa tccggagcag 60 gcgacagggc gcagaagcgg g atg tac ttctgt tgg ggc gcc gac tcc agg 111 Met Tyr Phe Cys Trp Gly Ala Asp Ser Arg1 5 10 gag ctg cag cgc cgg agg acg gcg ggc agc ccc ggg gct gag cta ctg159 Glu Leu Gln Arg Arg Arg Thr Ala Gly Ser Pro Gly Ala Glu Leu Leu 1520 25 cag gcg gcc agc ggg gag cgc cac tct ctg ctg ctg ctg acc aac cac207 Gln Ala Ala Ser Gly Glu Arg His Ser Leu Leu Leu Leu Thr Asn His 3035 40 agg gtc ctc tcg tgc gga gac aac agc agg ggt cag ctg ggc cgc agg255 Arg Val Leu Ser Cys Gly Asp Asn Ser Arg Gly Gln Leu Gly Arg Arg 4550 55 ggc gcg cag cgc ggg gag ctg cca gaa cca att cag gca ttg gaa acc303 Gly Ala Gln Arg Gly Glu Leu Pro Glu Pro Ile Gln Ala Leu Glu Thr 6065 70 cta att gtt gat ctc gtg agc tgc ggg aag gag cac tcc ctg gct gtg351 Leu Ile Val Asp Leu Val Ser Cys Gly Lys Glu His Ser Leu Ala Val 7580 85 90 tgc cac aaa gga agg gtc ttc gca tgg gga gct ggt tct gaa ggg cag399 Cys His Lys Gly Arg Val Phe Ala Trp Gly Ala Gly Ser Glu Gly Gln 95100 105 ctg ggg att gga gaa ttc aag gaa ata agt ttc aca cct aag aaa ata447 Leu Gly Ile Gly Glu Phe Lys Glu Ile Ser Phe Thr Pro Lys Lys Ile 110115 120 atg act ctg aat gat ata aaa ata ata caa gtt tcc tgt gga cac tac495 Met Thr Leu Asn Asp Ile Lys Ile Ile Gln Val Ser Cys Gly His Tyr 125130 135 cac tcc ctg gca tta tca aaa gat agc caa gtg ttt tcg tgg gga aag543 His Ser Leu Ala Leu Ser Lys Asp Ser Gln Val Phe Ser Trp Gly Lys 140145 150 aac agc cat ggg cag ctg ggc ttg ggg aag gag ttc ccc tcc caa gcc591 Asn Ser His Gly Gln Leu Gly Leu Gly Lys Glu Phe Pro Ser Gln Ala 155160 165 170 agc ccg cag agg gtg agg tcc ctg gag ggg atc cca ctg gct caggtg 639 Ser Pro Gln Arg Val Arg Ser Leu Glu Gly Ile Pro Leu Ala Gln Val175 180 185 gct gcc gga ggg gct cac agc ttt gcc ctg tct ctc tgt ggg acttcg 687 Ala Ala Gly Gly Ala His Ser Phe Ala Leu Ser Leu Cys Gly Thr Ser190 195 200 ttt ggc tgg gga agt aac agt gcc ggg cag ctg gcc ctc agt gggcgt 735 Phe Gly Trp Gly Ser Asn Ser Ala Gly Gln Leu Ala Leu Ser Gly Arg205 210 215 aat gtc cca gtg caa agc aac aag cct ctc tca gtc ggt gca ctgaag 783 Asn Val Pro Val Gln Ser Asn Lys Pro Leu Ser Val Gly Ala Leu Lys220 225 230 aat cta ggt gtg gtt tat atc agc tgt ggt gat gca cac act gcggtg 831 Asn Leu Gly Val Val Tyr Ile Ser Cys Gly Asp Ala His Thr Ala Val235 240 245 250 ctt acc cag gac ggg aaa gtg ttc aca ttt gga gac aat cgctct gga 879 Leu Thr Gln Asp Gly Lys Val Phe Thr Phe Gly Asp Asn Arg SerGly 255 260 265 cag ctg gga tac agc ccc act cct gag aag aga ggt cca caactt gtg 927 Gln Leu Gly Tyr Ser Pro Thr Pro Glu Lys Arg Gly Pro Gln LeuVal 270 275 280 gaa aga att gat ggc cta gtt tcg cag ata gat tgt gga agttat cac 975 Glu Arg Ile Asp Gly Leu Val Ser Gln Ile Asp Cys Gly Ser TyrHis 285 290 295 acc ctg gca tat gtg cac acc act ggt cag gtg gta tct tttggt cat 1023 Thr Leu Ala Tyr Val His Thr Thr Gly Gln Val Val Ser Phe GlyHis 300 305 310 gga cca agt gac aca agc aag cca act cat ccg gag gcc ctgaca gag 1071 Gly Pro Ser Asp Thr Ser Lys Pro Thr His Pro Glu Ala Leu ThrGlu 315 320 325 330 aac ttt gac att agc tgc ctg att tct gct gaa gac ttcgtg gat gtt 1119 Asn Phe Asp Ile Ser Cys Leu Ile Ser Ala Glu Asp Phe ValAsp Val 335 340 345 caa gtc aaa cac att ttt gct gga aca tat gcc aac tttgtg aca act 1167 Gln Val Lys His Ile Phe Ala Gly Thr Tyr Ala Asn Phe ValThr Thr 350 355 360 cat cag gat act agt tcc aca cgt gct ccc ggg aaa accctg cca gaa 1215 His Gln Asp Thr Ser Ser Thr Arg Ala Pro Gly Lys Thr LeuPro Glu 365 370 375 ata agc cga att agc cag tcc atg gca gaa aaa tgg atagca gtg aaa 1263 Ile Ser Arg Ile Ser Gln Ser Met Ala Glu Lys Trp Ile AlaVal Lys 380 385 390 aga aga agt act gaa cat gaa atg gct aaa agt gaa attaga atg ata 1311 Arg Arg Ser Thr Glu His Glu Met Ala Lys Ser Glu Ile ArgMet Ile 395 400 405 410 ttt tca tct cct gct tgt ctg act gca agt ttt ttaaag aaa aga gga 1359 Phe Ser Ser Pro Ala Cys Leu Thr Ala Ser Phe Leu LysLys Arg Gly 415 420 425 act gga gaa acg act tcc att gat gtg gac tta gaaatg gca aga gat 1407 Thr Gly Glu Thr Thr Ser Ile Asp Val Asp Leu Glu MetAla Arg Asp 430 435 440 acc ttc aag aag tta aca aaa aag gaa tgg att tcttcc atg ata act 1455 Thr Phe Lys Lys Leu Thr Lys Lys Glu Trp Ile Ser SerMet Ile Thr 445 450 455 acg tgt ctc gag gat gat ctg ctc aga gct ctt ccatgc cat tct cca 1503 Thr Cys Leu Glu Asp Asp Leu Leu Arg Ala Leu Pro CysHis Ser Pro 460 465 470 cac caa gaa gct tta tca gtt ttc ctc ctg ctc ccagaa tgt cct gtg 1551 His Gln Glu Ala Leu Ser Val Phe Leu Leu Leu Pro GluCys Pro Val 475 480 485 490 atg cat gat tct aag aac tgg aag aac ctg gtggtt cca ttt gca aag 1599 Met His Asp Ser Lys Asn Trp Lys Asn Leu Val ValPro Phe Ala Lys 495 500 505 gct gtg tgt gaa atg agt aaa caa tct ttg caagtc cta aag aag tgt 1647 Ala Val Cys Glu Met Ser Lys Gln Ser Leu Gln ValLeu Lys Lys Cys 510 515 520 tgg gca ttt ttg caa gaa tct tct ctg aat ccgctg atc cag atg ctt 1695 Trp Ala Phe Leu Gln Glu Ser Ser Leu Asn Pro LeuIle Gln Met Leu 525 530 535 aaa gca gcc atc atc tct cag ctg ctt cat cagact aaa acc gaa cag 1743 Lys Ala Ala Ile Ile Ser Gln Leu Leu His Gln ThrLys Thr Glu Gln 540 545 550 gat cac tgt aat gtt aaa gct ctt tta gga atgatg aaa gaa ctg cat 1791 Asp His Cys Asn Val Lys Ala Leu Leu Gly Met MetLys Glu Leu His 555 560 565 570 aag gta aac aaa gct aac tgt cga cta ccagaa aat act ttc aac ata 1839 Lys Val Asn Lys Ala Asn Cys Arg Leu Pro GluAsn Thr Phe Asn Ile 575 580 585 aat gaa ctc tcc aac tta tta aac ttt tatata gat aga gga aga cag 1887 Asn Glu Leu Ser Asn Leu Leu Asn Phe Tyr IleAsp Arg Gly Arg Gln 590 595 600 ctc ttt cgg gat aac cac ctg ata cct gcagaa acc ccc agt cct gtt 1935 Leu Phe Arg Asp Asn His Leu Ile Pro Ala GluThr Pro Ser Pro Val 605 610 615 att ttc agt gat ttt cca ttt atc ttt aattcg cta tcc aaa att aaa 1983 Ile Phe Ser Asp Phe Pro Phe Ile Phe Asn SerLeu Ser Lys Ile Lys 620 625 630 tta ttg caa gct gat tca cat ata aag atgcag atg tca gaa aag aaa 2031 Leu Leu Gln Ala Asp Ser His Ile Lys Met GlnMet Ser Glu Lys Lys 635 640 645 650 gca tac atg ctt atg cat gaa aca attctg caa aaa aag gat gaa ttt 2079 Ala Tyr Met Leu Met His Glu Thr Ile LeuGln Lys Lys Asp Glu Phe 655 660 665 cct cca tca ccc aga ttt ata ctt agagtc aga cga agt cgc ctg gtt 2127 Pro Pro Ser Pro Arg Phe Ile Leu Arg ValArg Arg Ser Arg Leu Val 670 675 680 aaa gat gct ctg cgt caa tta agt caagct gaa gct act gac ttc tgc 2175 Lys Asp Ala Leu Arg Gln Leu Ser Gln AlaGlu Ala Thr Asp Phe Cys 685 690 695 aaa gta tta gtg gtt gaa ttt att aatgaa att tgt cct gag tct gga 2223 Lys Val Leu Val Val Glu Phe Ile Asn GluIle Cys Pro Glu Ser Gly 700 705 710 ggg gtt agt tca gag ttc ttc cac tgtatg ttt gaa gag atg acc aag 2271 Gly Val Ser Ser Glu Phe Phe His Cys MetPhe Glu Glu Met Thr Lys 715 720 725 730 cca gaa tat gga atg ttc atg tatcct gaa atg ggt tcc tgc atg tgg 2319 Pro Glu Tyr Gly Met Phe Met Tyr ProGlu Met Gly Ser Cys Met Trp 735 740 745 ttt cct gcc aag cct aaa cct gagaag aaa aga tat ttc ctc ttt gga 2367 Phe Pro Ala Lys Pro Lys Pro Glu LysLys Arg Tyr Phe Leu Phe Gly 750 755 760 atg ctg tgt gga ctc tcc tta ttcaat tta aat gtt gct aac ctt cct 2415 Met Leu Cys Gly Leu Ser Leu Phe AsnLeu Asn Val Ala Asn Leu Pro 765 770 775 ttc cca ctg gct ctg tat aaa aaactt ctg gac caa aag cca tca ttg 2463 Phe Pro Leu Ala Leu Tyr Lys Lys LeuLeu Asp Gln Lys Pro Ser Leu 780 785 790 gaa gat tta aaa gaa ctc agt cctcgg ttg ggg aag agt ttg caa gaa 2511 Glu Asp Leu Lys Glu Leu Ser Pro ArgLeu Gly Lys Ser Leu Gln Glu 795 800 805 810 gtt cta gat gat gct gct gatgac att gga gat gcg ctc tgc ata cgc 2559 Val Leu Asp Asp Ala Ala Asp AspIle Gly Asp Ala Leu Cys Ile Arg 815 820 825 ttt tct ata cac tgg gac caaaat gat gtt gac tta att cca aat ggg 2607 Phe Ser Ile His Trp Asp Gln AsnAsp Val Asp Leu Ile Pro Asn Gly 830 835 840 atc tcc ata cct gtg gac caaacc aac aag aga gac tat gtt tct aag 2655 Ile Ser Ile Pro Val Asp Gln ThrAsn Lys Arg Asp Tyr Val Ser Lys 845 850 855 tat att gat tac att ttc aacgtc tct gta aaa gca gtt tat gag gaa 2703 Tyr Ile Asp Tyr Ile Phe Asn ValSer Val Lys Ala Val Tyr Glu Glu 860 865 870 ttt cag aga gga ttt tat agagtc tgt gag aag gag ata ctt aga cat 2751 Phe Gln Arg Gly Phe Tyr Arg ValCys Glu Lys Glu Ile Leu Arg His 875 880 885 890 ttc tac cct gaa gaa ctaatg aca gca atc att gga aat act gat tat 2799 Phe Tyr Pro Glu Glu Leu MetThr Ala Ile Ile Gly Asn Thr Asp Tyr 895 900 905 gac tgg aaa cag ttt gaacag aat tca aag tat gag caa gga tac caa 2847 Asp Trp Lys Gln Phe Glu GlnAsn Ser Lys Tyr Glu Gln Gly Tyr Gln 910 915 920 aaa tca cat cct act atacag ttg ttt tgg aag gct ttc cac aaa cta 2895 Lys Ser His Pro Thr Ile GlnLeu Phe Trp Lys Ala Phe His Lys Leu 925 930 935 acc ttg gat gaa aag aaaaaa ttc ctc ttt ttc ctt aca gga cgt gat 2943 Thr Leu Asp Glu Lys Lys LysPhe Leu Phe Phe Leu Thr Gly Arg Asp 940 945 950 agg ctg cat gca aga ggcata cag aaa atg gaa ata gta ttt cgc tgt 2991 Arg Leu His Ala Arg Gly IleGln Lys Met Glu Ile Val Phe Arg Cys 955 960 965 970 cct gaa act ttc agtgaa aga gat cac cca aca tca ata act tgt cat 3039 Pro Glu Thr Phe Ser GluArg Asp His Pro Thr Ser Ile Thr Cys His 975 980 985 aat att ctc tcc ctccct aag tat tct aca atg gaa aga atg gag gaa 3087 Asn Ile Leu Ser Leu ProLys Tyr Ser Thr Met Glu Arg Met Glu Glu 990 995 1000 gca ctt caa gta gccatc aac aac aac aga gga ttt gtc tca ccc atg 3135 Ala Leu Gln Val Ala IleAsn Asn Asn Arg Gly Phe Val Ser Pro Met 1005 1010 1015 ctc aca cag tcataa tcacctctga gagactcagg gtgggctttc tcacacttgg 3190 Leu Thr Gln Ser *1020 atccttctgt tcttccttac acctaaataa tacaagagat taatgaatag tggttagaag3250 tagttgaggg agagattggg ggaatgggga gatgatgatg atggtcaaag ggtgcaaaat3310 ctcacacaag actgaggcag gagaataggg tacagagata gggatctaag gatgacttgg3370 acacactccc tggcactgaa gagtctgaac actggcctgt gattggtcca ttccaggacc3430 ttcatttgca taaggtatca aaccacatca gcctctgatt ggccatgggc cagacctgca3490 ctctggccaa tgattggttc att 3513 30 1022 PRT Homo sapiens 30 Met TyrPhe Cys Trp Gly Ala Asp Ser Arg Glu Leu Gln Arg Arg Arg 1 5 10 15 ThrAla Gly Ser Pro Gly Ala Glu Leu Leu Gln Ala Ala Ser Gly Glu 20 25 30 ArgHis Ser Leu Leu Leu Leu Thr Asn His Arg Val Leu Ser Cys Gly 35 40 45 AspAsn Ser Arg Gly Gln Leu Gly Arg Arg Gly Ala Gln Arg Gly Glu 50 55 60 LeuPro Glu Pro Ile Gln Ala Leu Glu Thr Leu Ile Val Asp Leu Val 65 70 75 80Ser Cys Gly Lys Glu His Ser Leu Ala Val Cys His Lys Gly Arg Val 85 90 95Phe Ala Trp Gly Ala Gly Ser Glu Gly Gln Leu Gly Ile Gly Glu Phe 100 105110 Lys Glu Ile Ser Phe Thr Pro Lys Lys Ile Met Thr Leu Asn Asp Ile 115120 125 Lys Ile Ile Gln Val Ser Cys Gly His Tyr His Ser Leu Ala Leu Ser130 135 140 Lys Asp Ser Gln Val Phe Ser Trp Gly Lys Asn Ser His Gly GlnLeu 145 150 155 160 Gly Leu Gly Lys Glu Phe Pro Ser Gln Ala Ser Pro GlnArg Val Arg 165 170 175 Ser Leu Glu Gly Ile Pro Leu Ala Gln Val Ala AlaGly Gly Ala His 180 185 190 Ser Phe Ala Leu Ser Leu Cys Gly Thr Ser PheGly Trp Gly Ser Asn 195 200 205 Ser Ala Gly Gln Leu Ala Leu Ser Gly ArgAsn Val Pro Val Gln Ser 210 215 220 Asn Lys Pro Leu Ser Val Gly Ala LeuLys Asn Leu Gly Val Val Tyr 225 230 235 240 Ile Ser Cys Gly Asp Ala HisThr Ala Val Leu Thr Gln Asp Gly Lys 245 250 255 Val Phe Thr Phe Gly AspAsn Arg Ser Gly Gln Leu Gly Tyr Ser Pro 260 265 270 Thr Pro Glu Lys ArgGly Pro Gln Leu Val Glu Arg Ile Asp Gly Leu 275 280 285 Val Ser Gln IleAsp Cys Gly Ser Tyr His Thr Leu Ala Tyr Val His 290 295 300 Thr Thr GlyGln Val Val Ser Phe Gly His Gly Pro Ser Asp Thr Ser 305 310 315 320 LysPro Thr His Pro Glu Ala Leu Thr Glu Asn Phe Asp Ile Ser Cys 325 330 335Leu Ile Ser Ala Glu Asp Phe Val Asp Val Gln Val Lys His Ile Phe 340 345350 Ala Gly Thr Tyr Ala Asn Phe Val Thr Thr His Gln Asp Thr Ser Ser 355360 365 Thr Arg Ala Pro Gly Lys Thr Leu Pro Glu Ile Ser Arg Ile Ser Gln370 375 380 Ser Met Ala Glu Lys Trp Ile Ala Val Lys Arg Arg Ser Thr GluHis 385 390 395 400 Glu Met Ala Lys Ser Glu Ile Arg Met Ile Phe Ser SerPro Ala Cys 405 410 415 Leu Thr Ala Ser Phe Leu Lys Lys Arg Gly Thr GlyGlu Thr Thr Ser 420 425 430 Ile Asp Val Asp Leu Glu Met Ala Arg Asp ThrPhe Lys Lys Leu Thr 435 440 445 Lys Lys Glu Trp Ile Ser Ser Met Ile ThrThr Cys Leu Glu Asp Asp 450 455 460 Leu Leu Arg Ala Leu Pro Cys His SerPro His Gln Glu Ala Leu Ser 465 470 475 480 Val Phe Leu Leu Leu Pro GluCys Pro Val Met His Asp Ser Lys Asn 485 490 495 Trp Lys Asn Leu Val ValPro Phe Ala Lys Ala Val Cys Glu Met Ser 500 505 510 Lys Gln Ser Leu GlnVal Leu Lys Lys Cys Trp Ala Phe Leu Gln Glu 515 520 525 Ser Ser Leu AsnPro Leu Ile Gln Met Leu Lys Ala Ala Ile Ile Ser 530 535 540 Gln Leu LeuHis Gln Thr Lys Thr Glu Gln Asp His Cys Asn Val Lys 545 550 555 560 AlaLeu Leu Gly Met Met Lys Glu Leu His Lys Val Asn Lys Ala Asn 565 570 575Cys Arg Leu Pro Glu Asn Thr Phe Asn Ile Asn Glu Leu Ser Asn Leu 580 585590 Leu Asn Phe Tyr Ile Asp Arg Gly Arg Gln Leu Phe Arg Asp Asn His 595600 605 Leu Ile Pro Ala Glu Thr Pro Ser Pro Val Ile Phe Ser Asp Phe Pro610 615 620 Phe Ile Phe Asn Ser Leu Ser Lys Ile Lys Leu Leu Gln Ala AspSer 625 630 635 640 His Ile Lys Met Gln Met Ser Glu Lys Lys Ala Tyr MetLeu Met His 645 650 655 Glu Thr Ile Leu Gln Lys Lys Asp Glu Phe Pro ProSer Pro Arg Phe 660 665 670 Ile Leu Arg Val Arg Arg Ser Arg Leu Val LysAsp Ala Leu Arg Gln 675 680 685 Leu Ser Gln Ala Glu Ala Thr Asp Phe CysLys Val Leu Val Val Glu 690 695 700 Phe Ile Asn Glu Ile Cys Pro Glu SerGly Gly Val Ser Ser Glu Phe 705 710 715 720 Phe His Cys Met Phe Glu GluMet Thr Lys Pro Glu Tyr Gly Met Phe 725 730 735 Met Tyr Pro Glu Met GlySer Cys Met Trp Phe Pro Ala Lys Pro Lys 740 745 750 Pro Glu Lys Lys ArgTyr Phe Leu Phe Gly Met Leu Cys Gly Leu Ser 755 760 765 Leu Phe Asn LeuAsn Val Ala Asn Leu Pro Phe Pro Leu Ala Leu Tyr 770 775 780 Lys Lys LeuLeu Asp Gln Lys Pro Ser Leu Glu Asp Leu Lys Glu Leu 785 790 795 800 SerPro Arg Leu Gly Lys Ser Leu Gln Glu Val Leu Asp Asp Ala Ala 805 810 815Asp Asp Ile Gly Asp Ala Leu Cys Ile Arg Phe Ser Ile His Trp Asp 820 825830 Gln Asn Asp Val Asp Leu Ile Pro Asn Gly Ile Ser Ile Pro Val Asp 835840 845 Gln Thr Asn Lys Arg Asp Tyr Val Ser Lys Tyr Ile Asp Tyr Ile Phe850 855 860 Asn Val Ser Val Lys Ala Val Tyr Glu Glu Phe Gln Arg Gly PheTyr 865 870 875 880 Arg Val Cys Glu Lys Glu Ile Leu Arg His Phe Tyr ProGlu Glu Leu 885 890 895 Met Thr Ala Ile Ile Gly Asn Thr Asp Tyr Asp TrpLys Gln Phe Glu 900 905 910 Gln Asn Ser Lys Tyr Glu Gln Gly Tyr Gln LysSer His Pro Thr Ile 915 920 925 Gln Leu Phe Trp Lys Ala Phe His Lys LeuThr Leu Asp Glu Lys Lys 930 935 940 Lys Phe Leu Phe Phe Leu Thr Gly ArgAsp Arg Leu His Ala Arg Gly 945 950 955 960 Ile Gln Lys Met Glu Ile ValPhe Arg Cys Pro Glu Thr Phe Ser Glu 965 970 975 Arg Asp His Pro Thr SerIle Thr Cys His Asn Ile Leu Ser Leu Pro 980 985 990 Lys Tyr Ser Thr MetGlu Arg Met Glu Glu Ala Leu Gln Val Ala Ile 995 1000 1005 Asn Asn AsnArg Gly Phe Val Ser Pro Met Leu Thr Gln Ser 1010 1015 1020 31 3069 DNAHomo sapiens CDS (1)...(3069) 31 atg tac ttc tgt tgg ggc gcc gac tcc agggag ctg cag cgc cgg agg 48 Met Tyr Phe Cys Trp Gly Ala Asp Ser Arg GluLeu Gln Arg Arg Arg 1 5 10 15 acg gcg ggc agc ccc ggg gct gag cta ctgcag gcg gcc agc ggg gag 96 Thr Ala Gly Ser Pro Gly Ala Glu Leu Leu GlnAla Ala Ser Gly Glu 20 25 30 cgc cac tct ctg ctg ctg ctg acc aac cac agggtc ctc tcg tgc gga 144 Arg His Ser Leu Leu Leu Leu Thr Asn His Arg ValLeu Ser Cys Gly 35 40 45 gac aac agc agg ggt cag ctg ggc cgc agg ggc gcgcag cgc ggg gag 192 Asp Asn Ser Arg Gly Gln Leu Gly Arg Arg Gly Ala GlnArg Gly Glu 50 55 60 ctg cca gaa cca att cag gca ttg gaa acc cta att gttgat ctc gtg 240 Leu Pro Glu Pro Ile Gln Ala Leu Glu Thr Leu Ile Val AspLeu Val 65 70 75 80 agc tgc ggg aag gag cac tcc ctg gct gtg tgc cac aaagga agg gtc 288 Ser Cys Gly Lys Glu His Ser Leu Ala Val Cys His Lys GlyArg Val 85 90 95 ttc gca tgg gga gct ggt tct gaa ggg cag ctg ggg att ggagaa ttc 336 Phe Ala Trp Gly Ala Gly Ser Glu Gly Gln Leu Gly Ile Gly GluPhe 100 105 110 aag gaa ata agt ttc aca cct aag aaa ata atg act ctg aatgat ata 384 Lys Glu Ile Ser Phe Thr Pro Lys Lys Ile Met Thr Leu Asn AspIle 115 120 125 aaa ata ata caa gtt tcc tgt gga cac tac cac tcc ctg gcatta tca 432 Lys Ile Ile Gln Val Ser Cys Gly His Tyr His Ser Leu Ala LeuSer 130 135 140 aaa gat agc caa gtg ttt tcg tgg gga aag aac agc cat gggcag ctg 480 Lys Asp Ser Gln Val Phe Ser Trp Gly Lys Asn Ser His Gly GlnLeu 145 150 155 160 ggc ttg ggg aag gag ttc ccc tcc caa gcc agc ccg cagagg gtg agg 528 Gly Leu Gly Lys Glu Phe Pro Ser Gln Ala Ser Pro Gln ArgVal Arg 165 170 175 tcc ctg gag ggg atc cca ctg gct cag gtg gct gcc ggaggg gct cac 576 Ser Leu Glu Gly Ile Pro Leu Ala Gln Val Ala Ala Gly GlyAla His 180 185 190 agc ttt gcc ctg tct ctc tgt ggg act tcg ttt ggc tgggga agt aac 624 Ser Phe Ala Leu Ser Leu Cys Gly Thr Ser Phe Gly Trp GlySer Asn 195 200 205 agt gcc ggg cag ctg gcc ctc agt ggg cgt aat gtc ccagtg caa agc 672 Ser Ala Gly Gln Leu Ala Leu Ser Gly Arg Asn Val Pro ValGln Ser 210 215 220 aac aag cct ctc tca gtc ggt gca ctg aag aat cta ggtgtg gtt tat 720 Asn Lys Pro Leu Ser Val Gly Ala Leu Lys Asn Leu Gly ValVal Tyr 225 230 235 240 atc agc tgt ggt gat gca cac act gcg gtg ctt acccag gac ggg aaa 768 Ile Ser Cys Gly Asp Ala His Thr Ala Val Leu Thr GlnAsp Gly Lys 245 250 255 gtg ttc aca ttt gga gac aat cgc tct gga cag ctggga tac agc ccc 816 Val Phe Thr Phe Gly Asp Asn Arg Ser Gly Gln Leu GlyTyr Ser Pro 260 265 270 act cct gag aag aga ggt cca caa ctt gtg gaa agaatt gat ggc cta 864 Thr Pro Glu Lys Arg Gly Pro Gln Leu Val Glu Arg IleAsp Gly Leu 275 280 285 gtt tcg cag ata gat tgt gga agt tat cac acc ctggca tat gtg cac 912 Val Ser Gln Ile Asp Cys Gly Ser Tyr His Thr Leu AlaTyr Val His 290 295 300 acc act ggt cag gtg gta tct ttt ggt cat gga ccaagt gac aca agc 960 Thr Thr Gly Gln Val Val Ser Phe Gly His Gly Pro SerAsp Thr Ser 305 310 315 320 aag cca act cat ccg gag gcc ctg aca gag aacttt gac att agc tgc 1008 Lys Pro Thr His Pro Glu Ala Leu Thr Glu Asn PheAsp Ile Ser Cys 325 330 335 ctg att tct gct gaa gac ttc gtg gat gtt caagtc aaa cac att ttt 1056 Leu Ile Ser Ala Glu Asp Phe Val Asp Val Gln ValLys His Ile Phe 340 345 350 gct gga aca tat gcc aac ttt gtg aca act catcag gat act agt tcc 1104 Ala Gly Thr Tyr Ala Asn Phe Val Thr Thr His GlnAsp Thr Ser Ser 355 360 365 aca cgt gct ccc ggg aaa acc ctg cca gaa ataagc cga att agc cag 1152 Thr Arg Ala Pro Gly Lys Thr Leu Pro Glu Ile SerArg Ile Ser Gln 370 375 380 tcc atg gca gaa aaa tgg ata gca gtg aaa agaaga agt act gaa cat 1200 Ser Met Ala Glu Lys Trp Ile Ala Val Lys Arg ArgSer Thr Glu His 385 390 395 400 gaa atg gct aaa agt gaa att aga atg atattt tca tct cct gct tgt 1248 Glu Met Ala Lys Ser Glu Ile Arg Met Ile PheSer Ser Pro Ala Cys 405 410 415 ctg act gca agt ttt tta aag aaa aga ggaact gga gaa acg act tcc 1296 Leu Thr Ala Ser Phe Leu Lys Lys Arg Gly ThrGly Glu Thr Thr Ser 420 425 430 att gat gtg gac tta gaa atg gca aga gatacc ttc aag aag tta aca 1344 Ile Asp Val Asp Leu Glu Met Ala Arg Asp ThrPhe Lys Lys Leu Thr 435 440 445 aaa aag gaa tgg att tct tcc atg ata actacg tgt ctc gag gat gat 1392 Lys Lys Glu Trp Ile Ser Ser Met Ile Thr ThrCys Leu Glu Asp Asp 450 455 460 ctg ctc aga gct ctt cca tgc cat tct ccacac caa gaa gct tta tca 1440 Leu Leu Arg Ala Leu Pro Cys His Ser Pro HisGln Glu Ala Leu Ser 465 470 475 480 gtt ttc ctc ctg ctc cca gaa tgt cctgtg atg cat gat tct aag aac 1488 Val Phe Leu Leu Leu Pro Glu Cys Pro ValMet His Asp Ser Lys Asn 485 490 495 tgg aag aac ctg gtg gtt cca ttt gcaaag gct gtg tgt gaa atg agt 1536 Trp Lys Asn Leu Val Val Pro Phe Ala LysAla Val Cys Glu Met Ser 500 505 510 aaa caa tct ttg caa gtc cta aag aagtgt tgg gca ttt ttg caa gaa 1584 Lys Gln Ser Leu Gln Val Leu Lys Lys CysTrp Ala Phe Leu Gln Glu 515 520 525 tct tct ctg aat ccg ctg atc cag atgctt aaa gca gcc atc atc tct 1632 Ser Ser Leu Asn Pro Leu Ile Gln Met LeuLys Ala Ala Ile Ile Ser 530 535 540 cag ctg ctt cat cag act aaa acc gaacag gat cac tgt aat gtt aaa 1680 Gln Leu Leu His Gln Thr Lys Thr Glu GlnAsp His Cys Asn Val Lys 545 550 555 560 gct ctt tta gga atg atg aaa gaactg cat aag gta aac aaa gct aac 1728 Ala Leu Leu Gly Met Met Lys Glu LeuHis Lys Val Asn Lys Ala Asn 565 570 575 tgt cga cta cca gaa aat act ttcaac ata aat gaa ctc tcc aac tta 1776 Cys Arg Leu Pro Glu Asn Thr Phe AsnIle Asn Glu Leu Ser Asn Leu 580 585 590 tta aac ttt tat ata gat aga ggaaga cag ctc ttt cgg gat aac cac 1824 Leu Asn Phe Tyr Ile Asp Arg Gly ArgGln Leu Phe Arg Asp Asn His 595 600 605 ctg ata cct gca gaa acc ccc agtcct gtt att ttc agt gat ttt cca 1872 Leu Ile Pro Ala Glu Thr Pro Ser ProVal Ile Phe Ser Asp Phe Pro 610 615 620 ttt atc ttt aat tcg cta tcc aaaatt aaa tta ttg caa gct gat tca 1920 Phe Ile Phe Asn Ser Leu Ser Lys IleLys Leu Leu Gln Ala Asp Ser 625 630 635 640 cat ata aag atg cag atg tcagaa aag aaa gca tac atg ctt atg cat 1968 His Ile Lys Met Gln Met Ser GluLys Lys Ala Tyr Met Leu Met His 645 650 655 gaa aca att ctg caa aaa aaggat gaa ttt cct cca tca ccc aga ttt 2016 Glu Thr Ile Leu Gln Lys Lys AspGlu Phe Pro Pro Ser Pro Arg Phe 660 665 670 ata ctt aga gtc aga cga agtcgc ctg gtt aaa gat gct ctg cgt caa 2064 Ile Leu Arg Val Arg Arg Ser ArgLeu Val Lys Asp Ala Leu Arg Gln 675 680 685 tta agt caa gct gaa gct actgac ttc tgc aaa gta tta gtg gtt gaa 2112 Leu Ser Gln Ala Glu Ala Thr AspPhe Cys Lys Val Leu Val Val Glu 690 695 700 ttt att aat gaa att tgt cctgag tct gga ggg gtt agt tca gag ttc 2160 Phe Ile Asn Glu Ile Cys Pro GluSer Gly Gly Val Ser Ser Glu Phe 705 710 715 720 ttc cac tgt atg ttt gaagag atg acc aag cca gaa tat gga atg ttc 2208 Phe His Cys Met Phe Glu GluMet Thr Lys Pro Glu Tyr Gly Met Phe 725 730 735 atg tat cct gaa atg ggttcc tgc atg tgg ttt cct gcc aag cct aaa 2256 Met Tyr Pro Glu Met Gly SerCys Met Trp Phe Pro Ala Lys Pro Lys 740 745 750 cct gag aag aaa aga tatttc ctc ttt gga atg ctg tgt gga ctc tcc 2304 Pro Glu Lys Lys Arg Tyr PheLeu Phe Gly Met Leu Cys Gly Leu Ser 755 760 765 tta ttc aat tta aat gttgct aac ctt cct ttc cca ctg gct ctg tat 2352 Leu Phe Asn Leu Asn Val AlaAsn Leu Pro Phe Pro Leu Ala Leu Tyr 770 775 780 aaa aaa ctt ctg gac caaaag cca tca ttg gaa gat tta aaa gaa ctc 2400 Lys Lys Leu Leu Asp Gln LysPro Ser Leu Glu Asp Leu Lys Glu Leu 785 790 795 800 agt cct cgg ttg gggaag agt ttg caa gaa gtt cta gat gat gct gct 2448 Ser Pro Arg Leu Gly LysSer Leu Gln Glu Val Leu Asp Asp Ala Ala 805 810 815 gat gac att gga gatgcg ctc tgc ata cgc ttt tct ata cac tgg gac 2496 Asp Asp Ile Gly Asp AlaLeu Cys Ile Arg Phe Ser Ile His Trp Asp 820 825 830 caa aat gat gtt gactta att cca aat ggg atc tcc ata cct gtg gac 2544 Gln Asn Asp Val Asp LeuIle Pro Asn Gly Ile Ser Ile Pro Val Asp 835 840 845 caa acc aac aag agagac tat gtt tct aag tat att gat tac att ttc 2592 Gln Thr Asn Lys Arg AspTyr Val Ser Lys Tyr Ile Asp Tyr Ile Phe 850 855 860 aac gtc tct gta aaagca gtt tat gag gaa ttt cag aga gga ttt tat 2640 Asn Val Ser Val Lys AlaVal Tyr Glu Glu Phe Gln Arg Gly Phe Tyr 865 870 875 880 aga gtc tgt gagaag gag ata ctt aga cat ttc tac cct gaa gaa cta 2688 Arg Val Cys Glu LysGlu Ile Leu Arg His Phe Tyr Pro Glu Glu Leu 885 890 895 atg aca gca atcatt gga aat act gat tat gac tgg aaa cag ttt gaa 2736 Met Thr Ala Ile IleGly Asn Thr Asp Tyr Asp Trp Lys Gln Phe Glu 900 905 910 cag aat tca aagtat gag caa gga tac caa aaa tca cat cct act ata 2784 Gln Asn Ser Lys TyrGlu Gln Gly Tyr Gln Lys Ser His Pro Thr Ile 915 920 925 cag ttg ttt tggaag gct ttc cac aaa cta acc ttg gat gaa aag aaa 2832 Gln Leu Phe Trp LysAla Phe His Lys Leu Thr Leu Asp Glu Lys Lys 930 935 940 aaa ttc ctc tttttc ctt aca gga cgt gat agg ctg cat gca aga ggc 2880 Lys Phe Leu Phe PheLeu Thr Gly Arg Asp Arg Leu His Ala Arg Gly 945 950 955 960 ata cag aaaatg gaa ata gta ttt cgc tgt cct gaa act ttc agt gaa 2928 Ile Gln Lys MetGlu Ile Val Phe Arg Cys Pro Glu Thr Phe Ser Glu 965 970 975 aga gat caccca aca tca ata act tgt cat aat att ctc tcc ctc cct 2976 Arg Asp His ProThr Ser Ile Thr Cys His Asn Ile Leu Ser Leu Pro 980 985 990 aag tat tctaca atg gaa aga atg gag gaa gca ctt caa gta gcc atc 3024 Lys Tyr Ser ThrMet Glu Arg Met Glu Glu Ala Leu Gln Val Ala Ile 995 1000 1005 aac aacaac aga gga ttt gtc tca ccc atg ctc aca cag tca taa 3069 Asn Asn Asn ArgGly Phe Val Ser Pro Met Leu Thr Gln Ser * 1010 1015 1020 32 70 PRTArtificial Sequence Consensus sequence 32 Asp Gly Arg Val Tyr Ser LeuGly Cys Phe Arg Gly Glu Asn Gly Gln 1 5 10 15 Leu Gly Leu Gly Glu GluVal Glu Glu Ser Lys Gly Gly Arg Gln Gly 20 25 30 Leu Glu Arg Leu Leu ValPro Val Leu Val Met Leu Lys Ser Thr Ser 35 40 45 Ser Ser Leu Ser Glu LysVal Val Ser Val Ala Ser Gly Gly Gln His 50 55 60 Thr Val Ala Leu Thr Lys65 70 33 358 PRT Artificial Sequence Consensus sequence 33 Phe Leu ValSer Lys Glu Met Phe Asn Pro Met Tyr Gly Leu Phe Phe 1 5 10 15 Tyr SerPro Glu Ser Asp Arg Tyr Thr Leu Tyr Ile Asp Pro Asn Ser 20 25 30 Asp AspLys Thr Thr Leu Leu Phe Pro Glu Pro Leu Asn Pro Phe Lys 35 40 45 Ala AsnGlu Glu His Leu Glu Tyr Phe Lys Phe Ile Gly Arg Val Val 50 55 60 Gly LeuAla Leu Leu His Asn Arg Leu Leu Asp Leu Phe Phe Ala Arg 65 70 75 80 AlaPhe Tyr Lys Lys Leu Leu Arg Lys Ser Ile Lys Phe Val Thr Thr 85 90 95 ValPro Ser Asp Val Glu Thr Ser Phe His Asp Leu Glu Ser Val Asp 100 105 110Pro Glu Leu Tyr Asn Ser Leu Ile Lys Ile Leu Glu Asn Thr Glu Asp 115 120125 Lys Glu Phe Glu Glu Val Ile Asn Leu Thr Asp Leu Thr Phe Ser Ile 130135 140 Asp Leu Glu Glu Phe Gly Asn Asp Glu Lys Val Ser Lys Glu Tyr Val145 150 155 160 Thr Val Glu Leu Ile Pro Asn Gly Arg Asn Ile Val Val ThrLys Ser 165 170 175 Asn Lys Lys Glu Tyr Val His Leu Val Ile Gln Trp ArgLeu Val Lys 180 185 190 Arg Ile Glu Lys Gln Leu Lys Ala Phe Lys Glu GlyPhe Ser Glu Val 195 200 205 Ile Pro Glu Cys Asn Leu Ile Lys Ile Phe AsnGlu Glu Glu Leu Glu 210 215 220 Leu Leu Ile Gly Gly Val Glu Glu Glu GlyAsp Ile Asp Val Asp Asp 225 230 235 240 Leu Lys Ser Asn Thr Glu Tyr GluAsp Glu Ser Ser Glu Gly Tyr Ser 245 250 255 Glu Asp Ser Gln Val Ile GlnTrp Phe Trp Glu Ile Val Glu Glu Phe 260 265 270 Asp Lys Glu Glu Arg AlaLys Leu Leu Gln Phe Val Thr Gly Ser Pro 275 280 285 Arg Leu Pro Leu GlnGly Phe Lys Ser Leu Glu Gly Ser Asn Gly Ile 290 295 300 Pro Lys Phe ThrIle Glu Lys Ala Gly Thr Glu Asp Glu Arg Leu Pro 305 310 315 320 Thr AlaHis Thr Cys Phe Asn Arg Leu Asp Leu Pro Lys Tyr Ser Ser 325 330 335 LysGlu Ile Leu Arg Ser Lys Leu Leu Leu Ala Ile Glu Glu Cys Gly 340 345 350Glu Gly Phe Gly Leu Val 355 34 11 PRT Artificial Sequence ConservedRCC1_2 pattern 34 Xaa Xaa Xaa Gly Xaa Xaa His Xaa Xaa Xaa Xaa 1 5 10 353633 DNA Homo sapiens CDS (23)...(3415) 35 cgcaagcggg acactgtggt gg atgcaa ttc ccc tcg cct cca gcc gcg agg 52 Met Gln Phe Pro Ser Pro Pro AlaAla Arg 1 5 10 agc tcc ccg gcg ccg cag gca gcg tcc tcc tcc gaa gca gctgca cct 100 Ser Ser Pro Ala Pro Gln Ala Ala Ser Ser Ser Glu Ala Ala AlaPro 15 20 25 gca act ggg cag cct gga ccc tcg tgc cct gtt ccc ggg acc tcgcgc 148 Ala Thr Gly Gln Pro Gly Pro Ser Cys Pro Val Pro Gly Thr Ser Arg30 35 40 agg ggg cgc ccc ggg aca ccc cct gcg ggc cgg gtg gag gag gaa gag196 Arg Gly Arg Pro Gly Thr Pro Pro Ala Gly Arg Val Glu Glu Glu Glu 4550 55 gag gag gag gaa gaa gac gtg gac aag gac ccc cat cct acc cag aac244 Glu Glu Glu Glu Glu Asp Val Asp Lys Asp Pro His Pro Thr Gln Asn 6065 70 acc tgc ctg cgc tgc cgc cac ttc tct tta agg gag agg aaa aga gag292 Thr Cys Leu Arg Cys Arg His Phe Ser Leu Arg Glu Arg Lys Arg Glu 7580 85 90 cct agg aga acc atg ggg ggc tgc gaa gtc cgg gaa ttt ctt ttg caa340 Pro Arg Arg Thr Met Gly Gly Cys Glu Val Arg Glu Phe Leu Leu Gln 95100 105 ttt ggt ttc ttc ttg cct ctg ctg aca gcg tgg cca ggc gac tgc agt388 Phe Gly Phe Phe Leu Pro Leu Leu Thr Ala Trp Pro Gly Asp Cys Ser 110115 120 cac gtc tcc aac aac caa gtt gtg ttg ctt gat aca aca act gta ctg436 His Val Ser Asn Asn Gln Val Val Leu Leu Asp Thr Thr Thr Val Leu 125130 135 gga gag cta gga tgg aaa aca tat cca tta aat ggg tgg gat gcc atc484 Gly Glu Leu Gly Trp Lys Thr Tyr Pro Leu Asn Gly Trp Asp Ala Ile 140145 150 act gaa atg gat gaa cat aat agg ccc att cac aca tac cag gta tgt532 Thr Glu Met Asp Glu His Asn Arg Pro Ile His Thr Tyr Gln Val Cys 155160 165 170 aat gta atg gaa cca aac caa aac aac tgg ctt cgt aca aac tggatc 580 Asn Val Met Glu Pro Asn Gln Asn Asn Trp Leu Arg Thr Asn Trp Ile175 180 185 tcc cgt gat gca gct cag aaa att tat gtg gaa atg aaa ttc acacta 628 Ser Arg Asp Ala Ala Gln Lys Ile Tyr Val Glu Met Lys Phe Thr Leu190 195 200 agg gat tgt aac agc atc cca tgg gtc ttg ggg act tgc aaa gaaaca 676 Arg Asp Cys Asn Ser Ile Pro Trp Val Leu Gly Thr Cys Lys Glu Thr205 210 215 ttt aat ctg ttt tat atg gaa tca gat gag tcc cac gga att aaattc 724 Phe Asn Leu Phe Tyr Met Glu Ser Asp Glu Ser His Gly Ile Lys Phe220 225 230 aag cca aac cag tat aca aag atc gac aca att gct gct gat gagagt 772 Lys Pro Asn Gln Tyr Thr Lys Ile Asp Thr Ile Ala Ala Asp Glu Ser235 240 245 250 ttt acc cag atg gat ttg ggt gat cgc atc ctc aaa ctc aacact gaa 820 Phe Thr Gln Met Asp Leu Gly Asp Arg Ile Leu Lys Leu Asn ThrGlu 255 260 265 att cgt gag gtg ggg cct ata gaa agg aaa gga ttt tat ctggct ttt 868 Ile Arg Glu Val Gly Pro Ile Glu Arg Lys Gly Phe Tyr Leu AlaPhe 270 275 280 caa gac att ggg gcg tgc att gcc ctg gtt tca gtc cgt gttttc tac 916 Gln Asp Ile Gly Ala Cys Ile Ala Leu Val Ser Val Arg Val PheTyr 285 290 295 aag aaa tgc ccc ttc act gtt cgt aac ttg gcc atg ttt cctgat acc 964 Lys Lys Cys Pro Phe Thr Val Arg Asn Leu Ala Met Phe Pro AspThr 300 305 310 att cca agg gtt gat tcc tcc tct ttg gtt gaa gta cgg ggttct tgt 1012 Ile Pro Arg Val Asp Ser Ser Ser Leu Val Glu Val Arg Gly SerCys 315 320 325 330 gtg aag agt gct gaa gag cgt gac act cct aaa ctg tattgt gga gct 1060 Val Lys Ser Ala Glu Glu Arg Asp Thr Pro Lys Leu Tyr CysGly Ala 335 340 345 gat gga gat tgg ctg gtt cct ctt gga agg tgc atc tgcagt aca gga 1108 Asp Gly Asp Trp Leu Val Pro Leu Gly Arg Cys Ile Cys SerThr Gly 350 355 360 tat gaa gaa att gag ggt tct tgc cat gct tgc aga ccagga ttc tat 1156 Tyr Glu Glu Ile Glu Gly Ser Cys His Ala Cys Arg Pro GlyPhe Tyr 365 370 375 aaa gct ttt gct ggg aac aca aaa tgt tct aaa tgt cctcca cac agt 1204 Lys Ala Phe Ala Gly Asn Thr Lys Cys Ser Lys Cys Pro ProHis Ser 380 385 390 tta aca tac atg gaa gca act tct gtc tgt cag tgt gaaaag ggt tat 1252 Leu Thr Tyr Met Glu Ala Thr Ser Val Cys Gln Cys Glu LysGly Tyr 395 400 405 410 ttc cga gct gaa aaa gac cca cct tct atg gca tgtacc agg cca cct 1300 Phe Arg Ala Glu Lys Asp Pro Pro Ser Met Ala Cys ThrArg Pro Pro 415 420 425 tca gct cct agg aat gtg gtt ttt aac atc aat gaaaca gcc ctt att 1348 Ser Ala Pro Arg Asn Val Val Phe Asn Ile Asn Glu ThrAla Leu Ile 430 435 440 ttg gaa tgg agc cca cca agt gac aca gga ggg agaaaa gat ctc aca 1396 Leu Glu Trp Ser Pro Pro Ser Asp Thr Gly Gly Arg LysAsp Leu Thr 445 450 455 tac agt gta atc tgt aag aaa tgt ggc tta gac accagc cag tgt gag 1444 Tyr Ser Val Ile Cys Lys Lys Cys Gly Leu Asp Thr SerGln Cys Glu 460 465 470 gac tgt ggt gga gga ctc cgc ttc atc cca aga cataca ggc ctg atc 1492 Asp Cys Gly Gly Gly Leu Arg Phe Ile Pro Arg His ThrGly Leu Ile 475 480 485 490 aac aat tcc gtg ata gta ctt gac ttt gtg tctcac gtg aat tac acc 1540 Asn Asn Ser Val Ile Val Leu Asp Phe Val Ser HisVal Asn Tyr Thr 495 500 505 ttt gaa ata gaa gca atg aat gga gtt tct gagttg agt ttt tct ccc 1588 Phe Glu Ile Glu Ala Met Asn Gly Val Ser Glu LeuSer Phe Ser Pro 510 515 520 aag cca ttc aca gct att aca gtg acc acg gatcaa gat gca cct tcc 1636 Lys Pro Phe Thr Ala Ile Thr Val Thr Thr Asp GlnAsp Ala Pro Ser 525 530 535 ctg ata ggt gtg gta agg aag gac tgg gca tcccaa aat agc att gcc 1684 Leu Ile Gly Val Val Arg Lys Asp Trp Ala Ser GlnAsn Ser Ile Ala 540 545 550 cta tca tgg caa gca cct gct ttt tcc aat ggagcc att ctg gac tac 1732 Leu Ser Trp Gln Ala Pro Ala Phe Ser Asn Gly AlaIle Leu Asp Tyr 555 560 565 570 gag atc aag tac tat gag aag gaa cat gagcag ctg acc tac tct tcc 1780 Glu Ile Lys Tyr Tyr Glu Lys Glu His Glu GlnLeu Thr Tyr Ser Ser 575 580 585 aca agg tcc aaa gcc ccc agt gtc atc atcaca ggt ctt aag cca gcc 1828 Thr Arg Ser Lys Ala Pro Ser Val Ile Ile ThrGly Leu Lys Pro Ala 590 595 600 acc aaa tat gta ttt cac atc cga gtg agaact gcg aca gga tac agt 1876 Thr Lys Tyr Val Phe His Ile Arg Val Arg ThrAla Thr Gly Tyr Ser 605 610 615 ggc tac agt cag aaa ttt gaa ttt gaa acagga gat gaa act tct gac 1924 Gly Tyr Ser Gln Lys Phe Glu Phe Glu Thr GlyAsp Glu Thr Ser Asp 620 625 630 atg gca gca gaa caa gga cag att ctc gtgata gcc acc gcc gct gtt 1972 Met Ala Ala Glu Gln Gly Gln Ile Leu Val IleAla Thr Ala Ala Val 635 640 645 650 ggc gga ttc act ctc ctc gtc atc ctcact tta ttc ttc ttg atc act 2020 Gly Gly Phe Thr Leu Leu Val Ile Leu ThrLeu Phe Phe Leu Ile Thr 655 660 665 ggg aga tgt cag tgg tac ata aaa gccaag atg aag tca gaa gag aag 2068 Gly Arg Cys Gln Trp Tyr Ile Lys Ala LysMet Lys Ser Glu Glu Lys 670 675 680 aga aga aac cac tta cag aat ggg catttg cgc ttc ccg gga att aaa 2116 Arg Arg Asn His Leu Gln Asn Gly His LeuArg Phe Pro Gly Ile Lys 685 690 695 act tac att gat cca gat aca tat gaagac cca tcc cta gca gtc cat 2164 Thr Tyr Ile Asp Pro Asp Thr Tyr Glu AspPro Ser Leu Ala Val His 700 705 710 gaa ttt gca aag gag att gat ccc tcaaga att cgt att gag aga gtc 2212 Glu Phe Ala Lys Glu Ile Asp Pro Ser ArgIle Arg Ile Glu Arg Val 715 720 725 730 att ggg gca ggt gaa ttt gga gaagtc tgt agt ggg cgt ttg aag aca 2260 Ile Gly Ala Gly Glu Phe Gly Glu ValCys Ser Gly Arg Leu Lys Thr 735 740 745 cca ggg aaa aga gag atc cca gttgcc att aaa act ttg aaa ggt ggc 2308 Pro Gly Lys Arg Glu Ile Pro Val AlaIle Lys Thr Leu Lys Gly Gly 750 755 760 cac atg gat cgg caa aga aga gatttt cta aga gaa gct agt atc atg 2356 His Met Asp Arg Gln Arg Arg Asp PheLeu Arg Glu Ala Ser Ile Met 765 770 775 ggc cag ttt gac cat cca aac atcatt cgc cta gaa ggg gtt gtc acc 2404 Gly Gln Phe Asp His Pro Asn Ile IleArg Leu Glu Gly Val Val Thr 780 785 790 aaa aga tcc ttc ccg gcc att ggggtg gag gcg ttt tgc ccc agc ttc 2452 Lys Arg Ser Phe Pro Ala Ile Gly ValGlu Ala Phe Cys Pro Ser Phe 795 800 805 810 ctg agg gca ggg ttt tta aatagc atc cag gcc ccg cat cca gtg cca 2500 Leu Arg Ala Gly Phe Leu Asn SerIle Gln Ala Pro His Pro Val Pro 815 820 825 ggg gga gga tct ttg ccc cccagg att cct gct ggc aga cca gta atg 2548 Gly Gly Gly Ser Leu Pro Pro ArgIle Pro Ala Gly Arg Pro Val Met 830 835 840 att gtg gtg gaa tat atg gagaat gga tcc cta gac tcc ttt ttg cgg 2596 Ile Val Val Glu Tyr Met Glu AsnGly Ser Leu Asp Ser Phe Leu Arg 845 850 855 aag cat gat ggc cac ttc acagtc atc cag ttg gtc gga atg ctc cga 2644 Lys His Asp Gly His Phe Thr ValIle Gln Leu Val Gly Met Leu Arg 860 865 870 ggc att gca tca ggc atg aagtat ctt tct gat atg ggt tat gtt cat 2692 Gly Ile Ala Ser Gly Met Lys TyrLeu Ser Asp Met Gly Tyr Val His 875 880 885 890 cga gac cta gcg gct cggaat ata ctg gtc aat agc aac tta gta tgc 2740 Arg Asp Leu Ala Ala Arg AsnIle Leu Val Asn Ser Asn Leu Val Cys 895 900 905 aaa gtt tct gat ttt ggtctc tcc aga gtg ctg gaa gat gat cca gaa 2788 Lys Val Ser Asp Phe Gly LeuSer Arg Val Leu Glu Asp Asp Pro Glu 910 915 920 gct gct tat aca aca actggt gga aaa atc ccc ata agg tgg aca gcc 2836 Ala Ala Tyr Thr Thr Thr GlyGly Lys Ile Pro Ile Arg Trp Thr Ala 925 930 935 cca gaa gcc atc gcc tacaga aaa ttc tcc tca gca agc gat gca tgg 2884 Pro Glu Ala Ile Ala Tyr ArgLys Phe Ser Ser Ala Ser Asp Ala Trp 940 945 950 agc tat ggc att gtc atgtgg gag gtc atg tcc tat gga gag aga cct 2932 Ser Tyr Gly Ile Val Met TrpGlu Val Met Ser Tyr Gly Glu Arg Pro 955 960 965 970 tat tgg gaa atg tctaac caa gat gtc att ctg tcc att gaa gaa ggg 2980 Tyr Trp Glu Met Ser AsnGln Asp Val Ile Leu Ser Ile Glu Glu Gly 975 980 985 tac aga ctt cca gctccc atg ggc tgt cca gca tct cta cac cag ctg 3028 Tyr Arg Leu Pro Ala ProMet Gly Cys Pro Ala Ser Leu His Gln Leu 990 995 1000 atg ctc cac tgc tggcag aag gag aga aat cac aga cca aaa ttt act 3076 Met Leu His Cys Trp GlnLys Glu Arg Asn His Arg Pro Lys Phe Thr 1005 1010 1015 gac att gtc agcttc ctt gac aaa ctg atc cga aat ccc agt gcc ctt 3124 Asp Ile Val Ser PheLeu Asp Lys Leu Ile Arg Asn Pro Ser Ala Leu 1020 1025 1030 cac acc ctggtg gag gac atc ctt gta atg cca gag tcc cct ggt gaa 3172 His Thr Leu ValGlu Asp Ile Leu Val Met Pro Glu Ser Pro Gly Glu 1035 1040 1045 1050 gttccg gaa tat cct ttg ttt gtc aca gtt ggt gac tgg cta gat tct 3220 Val ProGlu Tyr Pro Leu Phe Val Thr Val Gly Asp Trp Leu Asp Ser 1055 1060 1065ata aag atg ggg caa tac aag aat aac ttc gtg gca gca ggg ttt aca 3268 IleLys Met Gly Gln Tyr Lys Asn Asn Phe Val Ala Ala Gly Phe Thr 1070 10751080 aca ttt gac ctg att tca aga atg agc att gat gac att aga aga att3316 Thr Phe Asp Leu Ile Ser Arg Met Ser Ile Asp Asp Ile Arg Arg Ile1085 1090 1095 gga gtc ata ctt att gga cac cag aga cga ata gtc agc agcata cag 3364 Gly Val Ile Leu Ile Gly His Gln Arg Arg Ile Val Ser Ser IleGln 1100 1105 1110 act tta cgt tta cac atg atg cac ata cag gag aag ggattt cat gta 3412 Thr Leu Arg Leu His Met Met His Ile Gln Glu Lys Gly PheHis Val 1115 1120 1125 1130 tga aagtaccaca agcacctgtg ttttgtgcctcagcatttct aaaatgaacg 3465 * atatcctctc tactactctc tcttctgatt ctccaaacatcacttcacaa actgcagtct 3525 tctgttcaga ctataggcac acaccttatg tttatgcttccaaccaggat tttaaaatca 3585 tgctacataa atccgttctg aataacctgc aactaaaaaaaaaaaaaa 3633 36 1130 PRT Homo sapiens 36 Met Gln Phe Pro Ser Pro ProAla Ala Arg Ser Ser Pro Ala Pro Gln 1 5 10 15 Ala Ala Ser Ser Ser GluAla Ala Ala Pro Ala Thr Gly Gln Pro Gly 20 25 30 Pro Ser Cys Pro Val ProGly Thr Ser Arg Arg Gly Arg Pro Gly Thr 35 40 45 Pro Pro Ala Gly Arg ValGlu Glu Glu Glu Glu Glu Glu Glu Glu Asp 50 55 60 Val Asp Lys Asp Pro HisPro Thr Gln Asn Thr Cys Leu Arg Cys Arg 65 70 75 80 His Phe Ser Leu ArgGlu Arg Lys Arg Glu Pro Arg Arg Thr Met Gly 85 90 95 Gly Cys Glu Val ArgGlu Phe Leu Leu Gln Phe Gly Phe Phe Leu Pro 100 105 110 Leu Leu Thr AlaTrp Pro Gly Asp Cys Ser His Val Ser Asn Asn Gln 115 120 125 Val Val LeuLeu Asp Thr Thr Thr Val Leu Gly Glu Leu Gly Trp Lys 130 135 140 Thr TyrPro Leu Asn Gly Trp Asp Ala Ile Thr Glu Met Asp Glu His 145 150 155 160Asn Arg Pro Ile His Thr Tyr Gln Val Cys Asn Val Met Glu Pro Asn 165 170175 Gln Asn Asn Trp Leu Arg Thr Asn Trp Ile Ser Arg Asp Ala Ala Gln 180185 190 Lys Ile Tyr Val Glu Met Lys Phe Thr Leu Arg Asp Cys Asn Ser Ile195 200 205 Pro Trp Val Leu Gly Thr Cys Lys Glu Thr Phe Asn Leu Phe TyrMet 210 215 220 Glu Ser Asp Glu Ser His Gly Ile Lys Phe Lys Pro Asn GlnTyr Thr 225 230 235 240 Lys Ile Asp Thr Ile Ala Ala Asp Glu Ser Phe ThrGln Met Asp Leu 245 250 255 Gly Asp Arg Ile Leu Lys Leu Asn Thr Glu IleArg Glu Val Gly Pro 260 265 270 Ile Glu Arg Lys Gly Phe Tyr Leu Ala PheGln Asp Ile Gly Ala Cys 275 280 285 Ile Ala Leu Val Ser Val Arg Val PheTyr Lys Lys Cys Pro Phe Thr 290 295 300 Val Arg Asn Leu Ala Met Phe ProAsp Thr Ile Pro Arg Val Asp Ser 305 310 315 320 Ser Ser Leu Val Glu ValArg Gly Ser Cys Val Lys Ser Ala Glu Glu 325 330 335 Arg Asp Thr Pro LysLeu Tyr Cys Gly Ala Asp Gly Asp Trp Leu Val 340 345 350 Pro Leu Gly ArgCys Ile Cys Ser Thr Gly Tyr Glu Glu Ile Glu Gly 355 360 365 Ser Cys HisAla Cys Arg Pro Gly Phe Tyr Lys Ala Phe Ala Gly Asn 370 375 380 Thr LysCys Ser Lys Cys Pro Pro His Ser Leu Thr Tyr Met Glu Ala 385 390 395 400Thr Ser Val Cys Gln Cys Glu Lys Gly Tyr Phe Arg Ala Glu Lys Asp 405 410415 Pro Pro Ser Met Ala Cys Thr Arg Pro Pro Ser Ala Pro Arg Asn Val 420425 430 Val Phe Asn Ile Asn Glu Thr Ala Leu Ile Leu Glu Trp Ser Pro Pro435 440 445 Ser Asp Thr Gly Gly Arg Lys Asp Leu Thr Tyr Ser Val Ile CysLys 450 455 460 Lys Cys Gly Leu Asp Thr Ser Gln Cys Glu Asp Cys Gly GlyGly Leu 465 470 475 480 Arg Phe Ile Pro Arg His Thr Gly Leu Ile Asn AsnSer Val Ile Val 485 490 495 Leu Asp Phe Val Ser His Val Asn Tyr Thr PheGlu Ile Glu Ala Met 500 505 510 Asn Gly Val Ser Glu Leu Ser Phe Ser ProLys Pro Phe Thr Ala Ile 515 520 525 Thr Val Thr Thr Asp Gln Asp Ala ProSer Leu Ile Gly Val Val Arg 530 535 540 Lys Asp Trp Ala Ser Gln Asn SerIle Ala Leu Ser Trp Gln Ala Pro 545 550 555 560 Ala Phe Ser Asn Gly AlaIle Leu Asp Tyr Glu Ile Lys Tyr Tyr Glu 565 570 575 Lys Glu His Glu GlnLeu Thr Tyr Ser Ser Thr Arg Ser Lys Ala Pro 580 585 590 Ser Val Ile IleThr Gly Leu Lys Pro Ala Thr Lys Tyr Val Phe His 595 600 605 Ile Arg ValArg Thr Ala Thr Gly Tyr Ser Gly Tyr Ser Gln Lys Phe 610 615 620 Glu PheGlu Thr Gly Asp Glu Thr Ser Asp Met Ala Ala Glu Gln Gly 625 630 635 640Gln Ile Leu Val Ile Ala Thr Ala Ala Val Gly Gly Phe Thr Leu Leu 645 650655 Val Ile Leu Thr Leu Phe Phe Leu Ile Thr Gly Arg Cys Gln Trp Tyr 660665 670 Ile Lys Ala Lys Met Lys Ser Glu Glu Lys Arg Arg Asn His Leu Gln675 680 685 Asn Gly His Leu Arg Phe Pro Gly Ile Lys Thr Tyr Ile Asp ProAsp 690 695 700 Thr Tyr Glu Asp Pro Ser Leu Ala Val His Glu Phe Ala LysGlu Ile 705 710 715 720 Asp Pro Ser Arg Ile Arg Ile Glu Arg Val Ile GlyAla Gly Glu Phe 725 730 735 Gly Glu Val Cys Ser Gly Arg Leu Lys Thr ProGly Lys Arg Glu Ile 740 745 750 Pro Val Ala Ile Lys Thr Leu Lys Gly GlyHis Met Asp Arg Gln Arg 755 760 765 Arg Asp Phe Leu Arg Glu Ala Ser IleMet Gly Gln Phe Asp His Pro 770 775 780 Asn Ile Ile Arg Leu Glu Gly ValVal Thr Lys Arg Ser Phe Pro Ala 785 790 795 800 Ile Gly Val Glu Ala PheCys Pro Ser Phe Leu Arg Ala Gly Phe Leu 805 810 815 Asn Ser Ile Gln AlaPro His Pro Val Pro Gly Gly Gly Ser Leu Pro 820 825 830 Pro Arg Ile ProAla Gly Arg Pro Val Met Ile Val Val Glu Tyr Met 835 840 845 Glu Asn GlySer Leu Asp Ser Phe Leu Arg Lys His Asp Gly His Phe 850 855 860 Thr ValIle Gln Leu Val Gly Met Leu Arg Gly Ile Ala Ser Gly Met 865 870 875 880Lys Tyr Leu Ser Asp Met Gly Tyr Val His Arg Asp Leu Ala Ala Arg 885 890895 Asn Ile Leu Val Asn Ser Asn Leu Val Cys Lys Val Ser Asp Phe Gly 900905 910 Leu Ser Arg Val Leu Glu Asp Asp Pro Glu Ala Ala Tyr Thr Thr Thr915 920 925 Gly Gly Lys Ile Pro Ile Arg Trp Thr Ala Pro Glu Ala Ile AlaTyr 930 935 940 Arg Lys Phe Ser Ser Ala Ser Asp Ala Trp Ser Tyr Gly IleVal Met 945 950 955 960 Trp Glu Val Met Ser Tyr Gly Glu Arg Pro Tyr TrpGlu Met Ser Asn 965 970 975 Gln Asp Val Ile Leu Ser Ile Glu Glu Gly TyrArg Leu Pro Ala Pro 980 985 990 Met Gly Cys Pro Ala Ser Leu His Gln LeuMet Leu His Cys Trp Gln 995 1000 1005 Lys Glu Arg Asn His Arg Pro LysPhe Thr Asp Ile Val Ser Phe Leu 1010 1015 1020 Asp Lys Leu Ile Arg AsnPro Ser Ala Leu His Thr Leu Val Glu Asp 1025 1030 1035 1040 Ile Leu ValMet Pro Glu Ser Pro Gly Glu Val Pro Glu Tyr Pro Leu 1045 1050 1055 PheVal Thr Val Gly Asp Trp Leu Asp Ser Ile Lys Met Gly Gln Tyr 1060 10651070 Lys Asn Asn Phe Val Ala Ala Gly Phe Thr Thr Phe Asp Leu Ile Ser1075 1080 1085 Arg Met Ser Ile Asp Asp Ile Arg Arg Ile Gly Val Ile LeuIle Gly 1090 1095 1100 His Gln Arg Arg Ile Val Ser Ser Ile Gln Thr LeuArg Leu His Met 1105 1110 1115 1120 Met His Ile Gln Glu Lys Gly Phe HisVal 1125 1130 37 3393 DNA Homo sapiens CDS (1)...(3393) 37 atg caa ttcccc tcg cct cca gcc gcg agg agc tcc ccg gcg ccg cag 48 Met Gln Phe ProSer Pro Pro Ala Ala Arg Ser Ser Pro Ala Pro Gln 1 5 10 15 gca gcg tcctcc tcc gaa gca gct gca cct gca act ggg cag cct gga 96 Ala Ala Ser SerSer Glu Ala Ala Ala Pro Ala Thr Gly Gln Pro Gly 20 25 30 ccc tcg tgc cctgtt ccc ggg acc tcg cgc agg ggg cgc ccc ggg aca 144 Pro Ser Cys Pro ValPro Gly Thr Ser Arg Arg Gly Arg Pro Gly Thr 35 40 45 ccc cct gcg ggc cgggtg gag gag gaa gag gag gag gag gaa gaa gac 192 Pro Pro Ala Gly Arg ValGlu Glu Glu Glu Glu Glu Glu Glu Glu Asp 50 55 60 gtg gac aag gac ccc catcct acc cag aac acc tgc ctg cgc tgc cgc 240 Val Asp Lys Asp Pro His ProThr Gln Asn Thr Cys Leu Arg Cys Arg 65 70 75 80 cac ttc tct tta agg gagagg aaa aga gag cct agg aga acc atg ggg 288 His Phe Ser Leu Arg Glu ArgLys Arg Glu Pro Arg Arg Thr Met Gly 85 90 95 ggc tgc gaa gtc cgg gaa tttctt ttg caa ttt ggt ttc ttc ttg cct 336 Gly Cys Glu Val Arg Glu Phe LeuLeu Gln Phe Gly Phe Phe Leu Pro 100 105 110 ctg ctg aca gcg tgg cca ggcgac tgc agt cac gtc tcc aac aac caa 384 Leu Leu Thr Ala Trp Pro Gly AspCys Ser His Val Ser Asn Asn Gln 115 120 125 gtt gtg ttg ctt gat aca acaact gta ctg gga gag cta gga tgg aaa 432 Val Val Leu Leu Asp Thr Thr ThrVal Leu Gly Glu Leu Gly Trp Lys 130 135 140 aca tat cca tta aat ggg tgggat gcc atc act gaa atg gat gaa cat 480 Thr Tyr Pro Leu Asn Gly Trp AspAla Ile Thr Glu Met Asp Glu His 145 150 155 160 aat agg ccc att cac acatac cag gta tgt aat gta atg gaa cca aac 528 Asn Arg Pro Ile His Thr TyrGln Val Cys Asn Val Met Glu Pro Asn 165 170 175 caa aac aac tgg ctt cgtaca aac tgg atc tcc cgt gat gca gct cag 576 Gln Asn Asn Trp Leu Arg ThrAsn Trp Ile Ser Arg Asp Ala Ala Gln 180 185 190 aaa att tat gtg gaa atgaaa ttc aca cta agg gat tgt aac agc atc 624 Lys Ile Tyr Val Glu Met LysPhe Thr Leu Arg Asp Cys Asn Ser Ile 195 200 205 cca tgg gtc ttg ggg acttgc aaa gaa aca ttt aat ctg ttt tat atg 672 Pro Trp Val Leu Gly Thr CysLys Glu Thr Phe Asn Leu Phe Tyr Met 210 215 220 gaa tca gat gag tcc cacgga att aaa ttc aag cca aac cag tat aca 720 Glu Ser Asp Glu Ser His GlyIle Lys Phe Lys Pro Asn Gln Tyr Thr 225 230 235 240 aag atc gac aca attgct gct gat gag agt ttt acc cag atg gat ttg 768 Lys Ile Asp Thr Ile AlaAla Asp Glu Ser Phe Thr Gln Met Asp Leu 245 250 255 ggt gat cgc atc ctcaaa ctc aac act gaa att cgt gag gtg ggg cct 816 Gly Asp Arg Ile Leu LysLeu Asn Thr Glu Ile Arg Glu Val Gly Pro 260 265 270 ata gaa agg aaa ggattt tat ctg gct ttt caa gac att ggg gcg tgc 864 Ile Glu Arg Lys Gly PheTyr Leu Ala Phe Gln Asp Ile Gly Ala Cys 275 280 285 att gcc ctg gtt tcagtc cgt gtt ttc tac aag aaa tgc ccc ttc act 912 Ile Ala Leu Val Ser ValArg Val Phe Tyr Lys Lys Cys Pro Phe Thr 290 295 300 gtt cgt aac ttg gccatg ttt cct gat acc att cca agg gtt gat tcc 960 Val Arg Asn Leu Ala MetPhe Pro Asp Thr Ile Pro Arg Val Asp Ser 305 310 315 320 tcc tct ttg gttgaa gta cgg ggt tct tgt gtg aag agt gct gaa gag 1008 Ser Ser Leu Val GluVal Arg Gly Ser Cys Val Lys Ser Ala Glu Glu 325 330 335 cgt gac act cctaaa ctg tat tgt gga gct gat gga gat tgg ctg gtt 1056 Arg Asp Thr Pro LysLeu Tyr Cys Gly Ala Asp Gly Asp Trp Leu Val 340 345 350 cct ctt gga aggtgc atc tgc agt aca gga tat gaa gaa att gag ggt 1104 Pro Leu Gly Arg CysIle Cys Ser Thr Gly Tyr Glu Glu Ile Glu Gly 355 360 365 tct tgc cat gcttgc aga cca gga ttc tat aaa gct ttt gct ggg aac 1152 Ser Cys His Ala CysArg Pro Gly Phe Tyr Lys Ala Phe Ala Gly Asn 370 375 380 aca aaa tgt tctaaa tgt cct cca cac agt tta aca tac atg gaa gca 1200 Thr Lys Cys Ser LysCys Pro Pro His Ser Leu Thr Tyr Met Glu Ala 385 390 395 400 act tct gtctgt cag tgt gaa aag ggt tat ttc cga gct gaa aaa gac 1248 Thr Ser Val CysGln Cys Glu Lys Gly Tyr Phe Arg Ala Glu Lys Asp 405 410 415 cca cct tctatg gca tgt acc agg cca cct tca gct cct agg aat gtg 1296 Pro Pro Ser MetAla Cys Thr Arg Pro Pro Ser Ala Pro Arg Asn Val 420 425 430 gtt ttt aacatc aat gaa aca gcc ctt att ttg gaa tgg agc cca cca 1344 Val Phe Asn IleAsn Glu Thr Ala Leu Ile Leu Glu Trp Ser Pro Pro 435 440 445 agt gac acagga ggg aga aaa gat ctc aca tac agt gta atc tgt aag 1392 Ser Asp Thr GlyGly Arg Lys Asp Leu Thr Tyr Ser Val Ile Cys Lys 450 455 460 aaa tgt ggctta gac acc agc cag tgt gag gac tgt ggt gga gga ctc 1440 Lys Cys Gly LeuAsp Thr Ser Gln Cys Glu Asp Cys Gly Gly Gly Leu 465 470 475 480 cgc ttcatc cca aga cat aca ggc ctg atc aac aat tcc gtg ata gta 1488 Arg Phe IlePro Arg His Thr Gly Leu Ile Asn Asn Ser Val Ile Val 485 490 495 ctt gacttt gtg tct cac gtg aat tac acc ttt gaa ata gaa gca atg 1536 Leu Asp PheVal Ser His Val Asn Tyr Thr Phe Glu Ile Glu Ala Met 500 505 510 aat ggagtt tct gag ttg agt ttt tct ccc aag cca ttc aca gct att 1584 Asn Gly ValSer Glu Leu Ser Phe Ser Pro Lys Pro Phe Thr Ala Ile 515 520 525 aca gtgacc acg gat caa gat gca cct tcc ctg ata ggt gtg gta agg 1632 Thr Val ThrThr Asp Gln Asp Ala Pro Ser Leu Ile Gly Val Val Arg 530 535 540 aag gactgg gca tcc caa aat agc att gcc cta tca tgg caa gca cct 1680 Lys Asp TrpAla Ser Gln Asn Ser Ile Ala Leu Ser Trp Gln Ala Pro 545 550 555 560 gctttt tcc aat gga gcc att ctg gac tac gag atc aag tac tat gag 1728 Ala PheSer Asn Gly Ala Ile Leu Asp Tyr Glu Ile Lys Tyr Tyr Glu 565 570 575 aaggaa cat gag cag ctg acc tac tct tcc aca agg tcc aaa gcc ccc 1776 Lys GluHis Glu Gln Leu Thr Tyr Ser Ser Thr Arg Ser Lys Ala Pro 580 585 590 agtgtc atc atc aca ggt ctt aag cca gcc acc aaa tat gta ttt cac 1824 Ser ValIle Ile Thr Gly Leu Lys Pro Ala Thr Lys Tyr Val Phe His 595 600 605 atccga gtg aga act gcg aca gga tac agt ggc tac agt cag aaa ttt 1872 Ile ArgVal Arg Thr Ala Thr Gly Tyr Ser Gly Tyr Ser Gln Lys Phe 610 615 620 gaattt gaa aca gga gat gaa act tct gac atg gca gca gaa caa gga 1920 Glu PheGlu Thr Gly Asp Glu Thr Ser Asp Met Ala Ala Glu Gln Gly 625 630 635 640cag att ctc gtg ata gcc acc gcc gct gtt ggc gga ttc act ctc ctc 1968 GlnIle Leu Val Ile Ala Thr Ala Ala Val Gly Gly Phe Thr Leu Leu 645 650 655gtc atc ctc act tta ttc ttc ttg atc act ggg aga tgt cag tgg tac 2016 ValIle Leu Thr Leu Phe Phe Leu Ile Thr Gly Arg Cys Gln Trp Tyr 660 665 670ata aaa gcc aag atg aag tca gaa gag aag aga aga aac cac tta cag 2064 IleLys Ala Lys Met Lys Ser Glu Glu Lys Arg Arg Asn His Leu Gln 675 680 685aat ggg cat ttg cgc ttc ccg gga att aaa act tac att gat cca gat 2112 AsnGly His Leu Arg Phe Pro Gly Ile Lys Thr Tyr Ile Asp Pro Asp 690 695 700aca tat gaa gac cca tcc cta gca gtc cat gaa ttt gca aag gag att 2160 ThrTyr Glu Asp Pro Ser Leu Ala Val His Glu Phe Ala Lys Glu Ile 705 710 715720 gat ccc tca aga att cgt att gag aga gtc att ggg gca ggt gaa ttt 2208Asp Pro Ser Arg Ile Arg Ile Glu Arg Val Ile Gly Ala Gly Glu Phe 725 730735 gga gaa gtc tgt agt ggg cgt ttg aag aca cca ggg aaa aga gag atc 2256Gly Glu Val Cys Ser Gly Arg Leu Lys Thr Pro Gly Lys Arg Glu Ile 740 745750 cca gtt gcc att aaa act ttg aaa ggt ggc cac atg gat cgg caa aga 2304Pro Val Ala Ile Lys Thr Leu Lys Gly Gly His Met Asp Arg Gln Arg 755 760765 aga gat ttt cta aga gaa gct agt atc atg ggc cag ttt gac cat cca 2352Arg Asp Phe Leu Arg Glu Ala Ser Ile Met Gly Gln Phe Asp His Pro 770 775780 aac atc att cgc cta gaa ggg gtt gtc acc aaa aga tcc ttc ccg gcc 2400Asn Ile Ile Arg Leu Glu Gly Val Val Thr Lys Arg Ser Phe Pro Ala 785 790795 800 att ggg gtg gag gcg ttt tgc ccc agc ttc ctg agg gca ggg ttt tta2448 Ile Gly Val Glu Ala Phe Cys Pro Ser Phe Leu Arg Ala Gly Phe Leu 805810 815 aat agc atc cag gcc ccg cat cca gtg cca ggg gga gga tct ttg ccc2496 Asn Ser Ile Gln Ala Pro His Pro Val Pro Gly Gly Gly Ser Leu Pro 820825 830 ccc agg att cct gct ggc aga cca gta atg att gtg gtg gaa tat atg2544 Pro Arg Ile Pro Ala Gly Arg Pro Val Met Ile Val Val Glu Tyr Met 835840 845 gag aat gga tcc cta gac tcc ttt ttg cgg aag cat gat ggc cac ttc2592 Glu Asn Gly Ser Leu Asp Ser Phe Leu Arg Lys His Asp Gly His Phe 850855 860 aca gtc atc cag ttg gtc gga atg ctc cga ggc att gca tca ggc atg2640 Thr Val Ile Gln Leu Val Gly Met Leu Arg Gly Ile Ala Ser Gly Met 865870 875 880 aag tat ctt tct gat atg ggt tat gtt cat cga gac cta gcg gctcgg 2688 Lys Tyr Leu Ser Asp Met Gly Tyr Val His Arg Asp Leu Ala Ala Arg885 890 895 aat ata ctg gtc aat agc aac tta gta tgc aaa gtt tct gat tttggt 2736 Asn Ile Leu Val Asn Ser Asn Leu Val Cys Lys Val Ser Asp Phe Gly900 905 910 ctc tcc aga gtg ctg gaa gat gat cca gaa gct gct tat aca acaact 2784 Leu Ser Arg Val Leu Glu Asp Asp Pro Glu Ala Ala Tyr Thr Thr Thr915 920 925 ggt gga aaa atc ccc ata agg tgg aca gcc cca gaa gcc atc gcctac 2832 Gly Gly Lys Ile Pro Ile Arg Trp Thr Ala Pro Glu Ala Ile Ala Tyr930 935 940 aga aaa ttc tcc tca gca agc gat gca tgg agc tat ggc att gtcatg 2880 Arg Lys Phe Ser Ser Ala Ser Asp Ala Trp Ser Tyr Gly Ile Val Met945 950 955 960 tgg gag gtc atg tcc tat gga gag aga cct tat tgg gaa atgtct aac 2928 Trp Glu Val Met Ser Tyr Gly Glu Arg Pro Tyr Trp Glu Met SerAsn 965 970 975 caa gat gtc att ctg tcc att gaa gaa ggg tac aga ctt ccagct ccc 2976 Gln Asp Val Ile Leu Ser Ile Glu Glu Gly Tyr Arg Leu Pro AlaPro 980 985 990 atg ggc tgt cca gca tct cta cac cag ctg atg ctc cac tgctgg cag 3024 Met Gly Cys Pro Ala Ser Leu His Gln Leu Met Leu His Cys TrpGln 995 1000 1005 aag gag aga aat cac aga cca aaa ttt act gac att gtcagc ttc ctt 3072 Lys Glu Arg Asn His Arg Pro Lys Phe Thr Asp Ile Val SerPhe Leu 1010 1015 1020 gac aaa ctg atc cga aat ccc agt gcc ctt cac accctg gtg gag gac 3120 Asp Lys Leu Ile Arg Asn Pro Ser Ala Leu His Thr LeuVal Glu Asp 1025 1030 1035 1040 atc ctt gta atg cca gag tcc cct ggt gaagtt ccg gaa tat cct ttg 3168 Ile Leu Val Met Pro Glu Ser Pro Gly Glu ValPro Glu Tyr Pro Leu 1045 1050 1055 ttt gtc aca gtt ggt gac tgg cta gattct ata aag atg ggg caa tac 3216 Phe Val Thr Val Gly Asp Trp Leu Asp SerIle Lys Met Gly Gln Tyr 1060 1065 1070 aag aat aac ttc gtg gca gca gggttt aca aca ttt gac ctg att tca 3264 Lys Asn Asn Phe Val Ala Ala Gly PheThr Thr Phe Asp Leu Ile Ser 1075 1080 1085 aga atg agc att gat gac attaga aga att gga gtc ata ctt att gga 3312 Arg Met Ser Ile Asp Asp Ile ArgArg Ile Gly Val Ile Leu Ile Gly 1090 1095 1100 cac cag aga cga ata gtcagc agc ata cag act tta cgt tta cac atg 3360 His Gln Arg Arg Ile Val SerSer Ile Gln Thr Leu Arg Leu His Met 1105 1110 1115 1120 atg cac ata caggag aag gga ttt cat gta tga 3393 Met His Ile Gln Glu Lys Gly Phe HisVal * 1125 1130 38 2466 DNA Homo sapiens CDS (437)...(1981) misc_feature(1)...(2466) n = A,T,C or G 38 gtccttctct aaggcgagct gcccttgggcgcgcctgggg ctgcacctgg gtcacgtggg 60 cgccgttgtg catgccggca cctcccggncaaccccgcgg cttggagaag gggctttgca 120 cccgccgccg ctgtttgtcc tcgcgcggcccccgtccact gccctgcggt tgctctgcgg 180 gctgaaaagt ttctcccggt gcagaattccgggctcagcg acagcctgcg ccgagtgtgc 240 gcacctgtcg gagacccgcc agtccgccggccgcgctctc acgtgtgaat atgtgtctag 300 tgcatcctta acctgaggac ttcaccagttcgaaattaca gttttcacca tcaactacct 360 tatccttttt ggtctggttt tcttcctcaaacagtggaaa catttttaaa gttgcttttg 420 ttgcagagtt aaacaa atg gct gat agtggc tta gat aaa aaa tcc aca aaa 472 Met Ala Asp Ser Gly Leu Asp Lys LysSer Thr Lys 1 5 10 tgc ccc gac tgt tca tct gct tct cag aaa gat gta ctttgt gta tgt 520 Cys Pro Asp Cys Ser Ser Ala Ser Gln Lys Asp Val Leu CysVal Cys 15 20 25 tcc agc aaa aca agg gtt cct cca gtt ttg gtg gtg gaa atgtca cag 568 Ser Ser Lys Thr Arg Val Pro Pro Val Leu Val Val Glu Met SerGln 30 35 40 aca tca agc att ggt agt gca gaa tct tta att tca ctg gag agaaaa 616 Thr Ser Ser Ile Gly Ser Ala Glu Ser Leu Ile Ser Leu Glu Arg Lys45 50 55 60 aaa gaa aaa aat atc aac aga gat ata acc tcc agg aaa gat ttgccc 664 Lys Glu Lys Asn Ile Asn Arg Asp Ile Thr Ser Arg Lys Asp Leu Pro65 70 75 tca aga acc tca aat gta gag aga aaa gca tct cag caa caa tgg ggt712 Ser Arg Thr Ser Asn Val Glu Arg Lys Ala Ser Gln Gln Gln Trp Gly 8085 90 cgg ggc aac ttt aca gaa gga aaa gtt cct cac ata agg att gag aat760 Arg Gly Asn Phe Thr Glu Gly Lys Val Pro His Ile Arg Ile Glu Asn 95100 105 gga gct gct att gag gaa atc tat acc ttt gga aga ata ttg gga aaa808 Gly Ala Ala Ile Glu Glu Ile Tyr Thr Phe Gly Arg Ile Leu Gly Lys 110115 120 ggg agc ttt gga ata gtc att gaa gcg aca gac aag gaa aca gaa acg856 Gly Ser Phe Gly Ile Val Ile Glu Ala Thr Asp Lys Glu Thr Glu Thr 125130 135 140 aag tgg gca att aaa aaa gtg aac aaa gaa aag gct gga agc tctgct 904 Lys Trp Ala Ile Lys Lys Val Asn Lys Glu Lys Ala Gly Ser Ser Ala145 150 155 gtg aag tta ctt gaa cga gag gtg aac att ctg aaa agt gta aaacat 952 Val Lys Leu Leu Glu Arg Glu Val Asn Ile Leu Lys Ser Val Lys His160 165 170 gaa cac atc ata cat ctg gaa caa gta ttt gaa acg cca aag aaaatg 1000 Glu His Ile Ile His Leu Glu Gln Val Phe Glu Thr Pro Lys Lys Met175 180 185 tac ctt gtg atg gag ctt tgt gag gat gga gaa ctc aaa gaa attctg 1048 Tyr Leu Val Met Glu Leu Cys Glu Asp Gly Glu Leu Lys Glu Ile Leu190 195 200 gat agg aaa ggg cat ttc tca gag aat gag aca agg tgg atc attcaa 1096 Asp Arg Lys Gly His Phe Ser Glu Asn Glu Thr Arg Trp Ile Ile Gln205 210 215 220 agt ctc gca tca gct ata gca tat ctt cac aat aat gat attgta cat 1144 Ser Leu Ala Ser Ala Ile Ala Tyr Leu His Asn Asn Asp Ile ValHis 225 230 235 aga gat ctg aaa ctg gaa aat ata atg gtt aaa agc agt cttatt gat 1192 Arg Asp Leu Lys Leu Glu Asn Ile Met Val Lys Ser Ser Leu IleAsp 240 245 250 gat aac aat gaa ata aac tta aac ata aag gtg act gat tttggc tta 1240 Asp Asn Asn Glu Ile Asn Leu Asn Ile Lys Val Thr Asp Phe GlyLeu 255 260 265 gcg gtg aag aag caa agt agg agt gaa gcc atg ctg cag gccaca tgt 1288 Ala Val Lys Lys Gln Ser Arg Ser Glu Ala Met Leu Gln Ala ThrCys 270 275 280 ggg act cct atc tat atg gcc cct gaa gtt atc agt gcc cacgac tat 1336 Gly Thr Pro Ile Tyr Met Ala Pro Glu Val Ile Ser Ala His AspTyr 285 290 295 300 agc cag cag tgt gac att tgg agc ata ggc gtc gta atgtac atg tta 1384 Ser Gln Gln Cys Asp Ile Trp Ser Ile Gly Val Val Met TyrMet Leu 305 310 315 tta cgt gga gaa cca ccc ttt ttg gca agc tca gaa gagaag ctt ttt 1432 Leu Arg Gly Glu Pro Pro Phe Leu Ala Ser Ser Glu Glu LysLeu Phe 320 325 330 gag tta ata aga aaa gga gaa cta cat ttt gaa aat gcagtc tgg aat 1480 Glu Leu Ile Arg Lys Gly Glu Leu His Phe Glu Asn Ala ValTrp Asn 335 340 345 tcc ata agt gac tgt gct aaa agt gtt ttg aaa caa cttatg aaa gta 1528 Ser Ile Ser Asp Cys Ala Lys Ser Val Leu Lys Gln Leu MetLys Val 350 355 360 gat cct gct cac aga atc aca gct aag gaa cta cta gataac cag tgg 1576 Asp Pro Ala His Arg Ile Thr Ala Lys Glu Leu Leu Asp AsnGln Trp 365 370 375 380 tta aca ggc aat aaa ctt tct tcg gtg aga cca accaat gta tta gag 1624 Leu Thr Gly Asn Lys Leu Ser Ser Val Arg Pro Thr AsnVal Leu Glu 385 390 395 atg atg aag gaa tgg aaa aat aac cca gaa agt gttgag gaa aac aca 1672 Met Met Lys Glu Trp Lys Asn Asn Pro Glu Ser Val GluGlu Asn Thr 400 405 410 aca gaa gag aag aat aag ccg tcc act gaa gaa aagttg aaa agt tac 1720 Thr Glu Glu Lys Asn Lys Pro Ser Thr Glu Glu Lys LeuLys Ser Tyr 415 420 425 caa ccc tgg gga aat gtc cct gat gcc aat tac acttca gat gaa gag 1768 Gln Pro Trp Gly Asn Val Pro Asp Ala Asn Tyr Thr SerAsp Glu Glu 430 435 440 gag gaa aaa cag tct act gct tat gaa aag caa tttcct gca acc agt 1816 Glu Glu Lys Gln Ser Thr Ala Tyr Glu Lys Gln Phe ProAla Thr Ser 445 450 455 460 aag gac aac ttt gat atg tgc agt tca agt ttcaca tct agc aaa ctc 1864 Lys Asp Asn Phe Asp Met Cys Ser Ser Ser Phe ThrSer Ser Lys Leu 465 470 475 ctt cca gct gaa atc aag gga gaa atg gag aaaacc cct gtg act cca 1912 Leu Pro Ala Glu Ile Lys Gly Glu Met Glu Lys ThrPro Val Thr Pro 480 485 490 agc caa gga aca gca acc aag tac cct gct aaatcc ggc gcc ctg tcc 1960 Ser Gln Gly Thr Ala Thr Lys Tyr Pro Ala Lys SerGly Ala Leu Ser 495 500 505 aga acc aaa aag aaa ctc taa ggttccctccagtgttggac agtacaaaaa 2011 Arg Thr Lys Lys Lys Leu * 510 caaagctgctcttgttagca ctttgatgag ggggtaggag gggaagaaga cagccctatg 2071 ctgagcttgtagccttttag ctccacagag ccccgccatg tgtttgcacc agcttaaaat 2131 tgaagctgcttatctccaaa gcagcataag ctgcacatgg cattaaagga cagccaccag 2191 taggcttggcagtgggctgc agtggaaatc aactcaagat gtacacgaag gttttttagg 2251 ggggcagataccttcaattt aaggctgtgg gcacacttgc tcatttttac ttcaaattct 2311 tatgtttaggcacagctatt tataggggaa aacaagaggc caaatatagt aatggaggtg 2371 ccaaataattatgtgcactt tgcactagaa gactttgtta gaaaattact aataaacttg 2431 ccatacgtattacaaaaaaa aaaaaaaaaa aaaaa 2466 39 514 PRT Homo sapiens 39 Met Ala AspSer Gly Leu Asp Lys Lys Ser Thr Lys Cys Pro Asp Cys 1 5 10 15 Ser SerAla Ser Gln Lys Asp Val Leu Cys Val Cys Ser Ser Lys Thr 20 25 30 Arg ValPro Pro Val Leu Val Val Glu Met Ser Gln Thr Ser Ser Ile 35 40 45 Gly SerAla Glu Ser Leu Ile Ser Leu Glu Arg Lys Lys Glu Lys Asn 50 55 60 Ile AsnArg Asp Ile Thr Ser Arg Lys Asp Leu Pro Ser Arg Thr Ser 65 70 75 80 AsnVal Glu Arg Lys Ala Ser Gln Gln Gln Trp Gly Arg Gly Asn Phe 85 90 95 ThrGlu Gly Lys Val Pro His Ile Arg Ile Glu Asn Gly Ala Ala Ile 100 105 110Glu Glu Ile Tyr Thr Phe Gly Arg Ile Leu Gly Lys Gly Ser Phe Gly 115 120125 Ile Val Ile Glu Ala Thr Asp Lys Glu Thr Glu Thr Lys Trp Ala Ile 130135 140 Lys Lys Val Asn Lys Glu Lys Ala Gly Ser Ser Ala Val Lys Leu Leu145 150 155 160 Glu Arg Glu Val Asn Ile Leu Lys Ser Val Lys His Glu HisIle Ile 165 170 175 His Leu Glu Gln Val Phe Glu Thr Pro Lys Lys Met TyrLeu Val Met 180 185 190 Glu Leu Cys Glu Asp Gly Glu Leu Lys Glu Ile LeuAsp Arg Lys Gly 195 200 205 His Phe Ser Glu Asn Glu Thr Arg Trp Ile IleGln Ser Leu Ala Ser 210 215 220 Ala Ile Ala Tyr Leu His Asn Asn Asp IleVal His Arg Asp Leu Lys 225 230 235 240 Leu Glu Asn Ile Met Val Lys SerSer Leu Ile Asp Asp Asn Asn Glu 245 250 255 Ile Asn Leu Asn Ile Lys ValThr Asp Phe Gly Leu Ala Val Lys Lys 260 265 270 Gln Ser Arg Ser Glu AlaMet Leu Gln Ala Thr Cys Gly Thr Pro Ile 275 280 285 Tyr Met Ala Pro GluVal Ile Ser Ala His Asp Tyr Ser Gln Gln Cys 290 295 300 Asp Ile Trp SerIle Gly Val Val Met Tyr Met Leu Leu Arg Gly Glu 305 310 315 320 Pro ProPhe Leu Ala Ser Ser Glu Glu Lys Leu Phe Glu Leu Ile Arg 325 330 335 LysGly Glu Leu His Phe Glu Asn Ala Val Trp Asn Ser Ile Ser Asp 340 345 350Cys Ala Lys Ser Val Leu Lys Gln Leu Met Lys Val Asp Pro Ala His 355 360365 Arg Ile Thr Ala Lys Glu Leu Leu Asp Asn Gln Trp Leu Thr Gly Asn 370375 380 Lys Leu Ser Ser Val Arg Pro Thr Asn Val Leu Glu Met Met Lys Glu385 390 395 400 Trp Lys Asn Asn Pro Glu Ser Val Glu Glu Asn Thr Thr GluGlu Lys 405 410 415 Asn Lys Pro Ser Thr Glu Glu Lys Leu Lys Ser Tyr GlnPro Trp Gly 420 425 430 Asn Val Pro Asp Ala Asn Tyr Thr Ser Asp Glu GluGlu Glu Lys Gln 435 440 445 Ser Thr Ala Tyr Glu Lys Gln Phe Pro Ala ThrSer Lys Asp Asn Phe 450 455 460 Asp Met Cys Ser Ser Ser Phe Thr Ser SerLys Leu Leu Pro Ala Glu 465 470 475 480 Ile Lys Gly Glu Met Glu Lys ThrPro Val Thr Pro Ser Gln Gly Thr 485 490 495 Ala Thr Lys Tyr Pro Ala LysSer Gly Ala Leu Ser Arg Thr Lys Lys 500 505 510 Lys Leu 40 1545 DNA Homosapiens CDS (1)...(1545) 40 atg gct gat agt ggc tta gat aaa aaa tcc acaaaa tgc ccc gac tgt 48 Met Ala Asp Ser Gly Leu Asp Lys Lys Ser Thr LysCys Pro Asp Cys 1 5 10 15 tca tct gct tct cag aaa gat gta ctt tgt gtatgt tcc agc aaa aca 96 Ser Ser Ala Ser Gln Lys Asp Val Leu Cys Val CysSer Ser Lys Thr 20 25 30 agg gtt cct cca gtt ttg gtg gtg gaa atg tca cagaca tca agc att 144 Arg Val Pro Pro Val Leu Val Val Glu Met Ser Gln ThrSer Ser Ile 35 40 45 ggt agt gca gaa tct tta att tca ctg gag aga aaa aaagaa aaa aat 192 Gly Ser Ala Glu Ser Leu Ile Ser Leu Glu Arg Lys Lys GluLys Asn 50 55 60 atc aac aga gat ata acc tcc agg aaa gat ttg ccc tca agaacc tca 240 Ile Asn Arg Asp Ile Thr Ser Arg Lys Asp Leu Pro Ser Arg ThrSer 65 70 75 80 aat gta gag aga aaa gca tct cag caa caa tgg ggt cgg ggcaac ttt 288 Asn Val Glu Arg Lys Ala Ser Gln Gln Gln Trp Gly Arg Gly AsnPhe 85 90 95 aca gaa gga aaa gtt cct cac ata agg att gag aat gga gct gctatt 336 Thr Glu Gly Lys Val Pro His Ile Arg Ile Glu Asn Gly Ala Ala Ile100 105 110 gag gaa atc tat acc ttt gga aga ata ttg gga aaa ggg agc tttgga 384 Glu Glu Ile Tyr Thr Phe Gly Arg Ile Leu Gly Lys Gly Ser Phe Gly115 120 125 ata gtc att gaa gcg aca gac aag gaa aca gaa acg aag tgg gcaatt 432 Ile Val Ile Glu Ala Thr Asp Lys Glu Thr Glu Thr Lys Trp Ala Ile130 135 140 aaa aaa gtg aac aaa gaa aag gct gga agc tct gct gtg aag ttactt 480 Lys Lys Val Asn Lys Glu Lys Ala Gly Ser Ser Ala Val Lys Leu Leu145 150 155 160 gaa cga gag gtg aac att ctg aaa agt gta aaa cat gaa cacatc ata 528 Glu Arg Glu Val Asn Ile Leu Lys Ser Val Lys His Glu His IleIle 165 170 175 cat ctg gaa caa gta ttt gaa acg cca aag aaa atg tac cttgtg atg 576 His Leu Glu Gln Val Phe Glu Thr Pro Lys Lys Met Tyr Leu ValMet 180 185 190 gag ctt tgt gag gat gga gaa ctc aaa gaa att ctg gat aggaaa ggg 624 Glu Leu Cys Glu Asp Gly Glu Leu Lys Glu Ile Leu Asp Arg LysGly 195 200 205 cat ttc tca gag aat gag aca agg tgg atc att caa agt ctcgca tca 672 His Phe Ser Glu Asn Glu Thr Arg Trp Ile Ile Gln Ser Leu AlaSer 210 215 220 gct ata gca tat ctt cac aat aat gat att gta cat aga gatctg aaa 720 Ala Ile Ala Tyr Leu His Asn Asn Asp Ile Val His Arg Asp LeuLys 225 230 235 240 ctg gaa aat ata atg gtt aaa agc agt ctt att gat gataac aat gaa 768 Leu Glu Asn Ile Met Val Lys Ser Ser Leu Ile Asp Asp AsnAsn Glu 245 250 255 ata aac tta aac ata aag gtg act gat ttt ggc tta gcggtg aag aag 816 Ile Asn Leu Asn Ile Lys Val Thr Asp Phe Gly Leu Ala ValLys Lys 260 265 270 caa agt agg agt gaa gcc atg ctg cag gcc aca tgt gggact cct atc 864 Gln Ser Arg Ser Glu Ala Met Leu Gln Ala Thr Cys Gly ThrPro Ile 275 280 285 tat atg gcc cct gaa gtt atc agt gcc cac gac tat agccag cag tgt 912 Tyr Met Ala Pro Glu Val Ile Ser Ala His Asp Tyr Ser GlnGln Cys 290 295 300 gac att tgg agc ata ggc gtc gta atg tac atg tta ttacgt gga gaa 960 Asp Ile Trp Ser Ile Gly Val Val Met Tyr Met Leu Leu ArgGly Glu 305 310 315 320 cca ccc ttt ttg gca agc tca gaa gag aag ctt tttgag tta ata aga 1008 Pro Pro Phe Leu Ala Ser Ser Glu Glu Lys Leu Phe GluLeu Ile Arg 325 330 335 aaa gga gaa cta cat ttt gaa aat gca gtc tgg aattcc ata agt gac 1056 Lys Gly Glu Leu His Phe Glu Asn Ala Val Trp Asn SerIle Ser Asp 340 345 350 tgt gct aaa agt gtt ttg aaa caa ctt atg aaa gtagat cct gct cac 1104 Cys Ala Lys Ser Val Leu Lys Gln Leu Met Lys Val AspPro Ala His 355 360 365 aga atc aca gct aag gaa cta cta gat aac cag tggtta aca ggc aat 1152 Arg Ile Thr Ala Lys Glu Leu Leu Asp Asn Gln Trp LeuThr Gly Asn 370 375 380 aaa ctt tct tcg gtg aga cca acc aat gta tta gagatg atg aag gaa 1200 Lys Leu Ser Ser Val Arg Pro Thr Asn Val Leu Glu MetMet Lys Glu 385 390 395 400 tgg aaa aat aac cca gaa agt gtt gag gaa aacaca aca gaa gag aag 1248 Trp Lys Asn Asn Pro Glu Ser Val Glu Glu Asn ThrThr Glu Glu Lys 405 410 415 aat aag ccg tcc act gaa gaa aag ttg aaa agttac caa ccc tgg gga 1296 Asn Lys Pro Ser Thr Glu Glu Lys Leu Lys Ser TyrGln Pro Trp Gly 420 425 430 aat gtc cct gat gcc aat tac act tca gat gaagag gag gaa aaa cag 1344 Asn Val Pro Asp Ala Asn Tyr Thr Ser Asp Glu GluGlu Glu Lys Gln 435 440 445 tct act gct tat gaa aag caa ttt cct gca accagt aag gac aac ttt 1392 Ser Thr Ala Tyr Glu Lys Gln Phe Pro Ala Thr SerLys Asp Asn Phe 450 455 460 gat atg tgc agt tca agt ttc aca tct agc aaactc ctt cca gct gaa 1440 Asp Met Cys Ser Ser Ser Phe Thr Ser Ser Lys LeuLeu Pro Ala Glu 465 470 475 480 atc aag gga gaa atg gag aaa acc cct gtgact cca agc caa gga aca 1488 Ile Lys Gly Glu Met Glu Lys Thr Pro Val ThrPro Ser Gln Gly Thr 485 490 495 gca acc aag tac cct gct aaa tcc ggc gccctg tcc aga acc aaa aag 1536 Ala Thr Lys Tyr Pro Ala Lys Ser Gly Ala LeuSer Arg Thr Lys Lys 500 505 510 aaa ctc taa 1545 Lys Leu * 41 2711 DNAHomo sapiens CDS (198)...(1883) misc_feature (1)...(2711) n = A,T,C or G41 cgcgtccgaa aaaaaaaaaa aaaaaaaaaa aangggctgn gctcsrcgmt yccggcccca 60gcgaggcggt ggggcggggc ggggcggggc ggggcgcgca gcaggagcga gtggggccgc 120cgccgggccg cggacactgt cgcccggcgc ccaggttccc aacaaggcta cgcagaagaa 180cccccttgac tgaagca atg gag ggg ggt cca gct gtc tgc tgc cag gat 230 MetGlu Gly Gly Pro Ala Val Cys Cys Gln Asp 1 5 10 cct cgg gca gag ctg gtagaa cgg gtg gca gcc atc gat gtg act cac 278 Pro Arg Ala Glu Leu Val GluArg Val Ala Ala Ile Asp Val Thr His 15 20 25 ttg gag gag gca gat ggt ggccca gag cct act aga aac ggt gtg gac 326 Leu Glu Glu Ala Asp Gly Gly ProGlu Pro Thr Arg Asn Gly Val Asp 30 35 40 ccc cca cca cgg gcc aga gct gcctct gtg atc cct ggc agt act tca 374 Pro Pro Pro Arg Ala Arg Ala Ala SerVal Ile Pro Gly Ser Thr Ser 45 50 55 aga ctg ctc cca gcc cgg cct agc ctctca gcc agg aag ctt tcc cta 422 Arg Leu Leu Pro Ala Arg Pro Ser Leu SerAla Arg Lys Leu Ser Leu 60 65 70 75 cag gag cgg cca gca gga agc tat ctggag gcg cag gct ggg cct tat 470 Gln Glu Arg Pro Ala Gly Ser Tyr Leu GluAla Gln Ala Gly Pro Tyr 80 85 90 gcc acg ggg cct gcc agc cac atc tcc ccccgg gcc tgg cgg agg ccc 518 Ala Thr Gly Pro Ala Ser His Ile Ser Pro ArgAla Trp Arg Arg Pro 95 100 105 acc atc gag tcc cac cac gtg gcc atc tcagat gca gag gac tgc gtg 566 Thr Ile Glu Ser His His Val Ala Ile Ser AspAla Glu Asp Cys Val 110 115 120 cag ctg aac cag tac aag ctg cag agt gagatt ggc aag ggt gcc tac 614 Gln Leu Asn Gln Tyr Lys Leu Gln Ser Glu IleGly Lys Gly Ala Tyr 125 130 135 ggt gtg gtg agg ctg gcc tac aac gaa agtgaa gac aga cac tat gca 662 Gly Val Val Arg Leu Ala Tyr Asn Glu Ser GluAsp Arg His Tyr Ala 140 145 150 155 atg aaa gtc ctt tcc aaa aag aag ttactg aag cag tat ggc ttt cca 710 Met Lys Val Leu Ser Lys Lys Lys Leu LeuLys Gln Tyr Gly Phe Pro 160 165 170 cgt cgc cct ccc cca aga ggg tcc caggct gcc cag gga gga cca gcc 758 Arg Arg Pro Pro Pro Arg Gly Ser Gln AlaAla Gln Gly Gly Pro Ala 175 180 185 aag cag ctg ctg ccc ctg gag cgg gtgtac cag gag att gcc atc ctg 806 Lys Gln Leu Leu Pro Leu Glu Arg Val TyrGln Glu Ile Ala Ile Leu 190 195 200 aag aag ctg gac cac gtg aat gtg gtcaaa ctg atc gag gtc ctg gat 854 Lys Lys Leu Asp His Val Asn Val Val LysLeu Ile Glu Val Leu Asp 205 210 215 gac cca gct gag gac aac ctc tat ttggtg ttt gac ctc ctg aga aag 902 Asp Pro Ala Glu Asp Asn Leu Tyr Leu ValPhe Asp Leu Leu Arg Lys 220 225 230 235 ggg ccc gtc atg gaa gtg ccc tgtgac aag ccc ttc tcg gag gag caa 950 Gly Pro Val Met Glu Val Pro Cys AspLys Pro Phe Ser Glu Glu Gln 240 245 250 gct cgc ctc tac ctg cgg gac gtcatc ctg ggc ctc gag tac ttg cac 998 Ala Arg Leu Tyr Leu Arg Asp Val IleLeu Gly Leu Glu Tyr Leu His 255 260 265 tgc cag aag atc gtc cac agg gacatc aag cca tcc aac ctg ctc ctg 1046 Cys Gln Lys Ile Val His Arg Asp IleLys Pro Ser Asn Leu Leu Leu 270 275 280 ggg gat gat ggg cac gtg aag atcgcc gac ttt ggc gtc agc aac cag 1094 Gly Asp Asp Gly His Val Lys Ile AlaAsp Phe Gly Val Ser Asn Gln 285 290 295 ttt gag ggg aac gac gct cag ctgtcc agc acg gcg gga acc cca gca 1142 Phe Glu Gly Asn Asp Ala Gln Leu SerSer Thr Ala Gly Thr Pro Ala 300 305 310 315 ttc atg gcc ccc gag gcc atttct gat tcc ggc cag agc ttc agt ggg 1190 Phe Met Ala Pro Glu Ala Ile SerAsp Ser Gly Gln Ser Phe Ser Gly 320 325 330 aag gcc ttg gat gta tgg gccact ggc gtc acg ttg tac tgc ttt gtc 1238 Lys Ala Leu Asp Val Trp Ala ThrGly Val Thr Leu Tyr Cys Phe Val 335 340 345 tat ggg aag tgc ccg ttc atcgac gat ttc atc ctg gcc ctc cac agg 1286 Tyr Gly Lys Cys Pro Phe Ile AspAsp Phe Ile Leu Ala Leu His Arg 350 355 360 aag atc aag aat gag ccc gtggtg ttt cct gag ggg cca gaa atc agc 1334 Lys Ile Lys Asn Glu Pro Val ValPhe Pro Glu Gly Pro Glu Ile Ser 365 370 375 gag gag ctc aag gac ctg atcctg aag atg tta gac aag aat ccc gag 1382 Glu Glu Leu Lys Asp Leu Ile LeuLys Met Leu Asp Lys Asn Pro Glu 380 385 390 395 acg aga att ggg gtg ccagac atc aag ttg cac cct tgg gtg acc aag 1430 Thr Arg Ile Gly Val Pro AspIle Lys Leu His Pro Trp Val Thr Lys 400 405 410 aac ggg gag gag ccc cttcct tcg gag gag gag cac tgc agc gtg gtg 1478 Asn Gly Glu Glu Pro Leu ProSer Glu Glu Glu His Cys Ser Val Val 415 420 425 gag gtg aca gag gag gaggtt aag aac tca gtc agg ctc atc ccc agc 1526 Glu Val Thr Glu Glu Glu ValLys Asn Ser Val Arg Leu Ile Pro Ser 430 435 440 tgg acc acg gtg atc ctggtg aag tcc atg ctg agg aag cgt tcc ttt 1574 Trp Thr Thr Val Ile Leu ValLys Ser Met Leu Arg Lys Arg Ser Phe 445 450 455 ggg aac ccg ttt gag ccccaa gca cgg agg gaa gag cga tcc atg tct 1622 Gly Asn Pro Phe Glu Pro GlnAla Arg Arg Glu Glu Arg Ser Met Ser 460 465 470 475 gct cca gga aac ctactg gtg aaa gaa ggg ttt ggt gaa ggg ggc aag 1670 Ala Pro Gly Asn Leu LeuVal Lys Glu Gly Phe Gly Glu Gly Gly Lys 480 485 490 agc cca gag ctc cccggc gtc cag gct tac cac aac gga aga gac ctc 1718 Ser Pro Glu Leu Pro GlyVal Gln Ala Tyr His Asn Gly Arg Asp Leu 495 500 505 ccg ctg ggg ccg ggcagg cct ggc tca gct gcc aca ggc ata tgg tgg 1766 Pro Leu Gly Pro Gly ArgPro Gly Ser Ala Ala Thr Gly Ile Trp Trp 510 515 520 aga ggg ggg tac cctgcc cac ctt ggg gtg gtg gca cca gag ctc ttg 1814 Arg Gly Gly Tyr Pro AlaHis Leu Gly Val Val Ala Pro Glu Leu Leu 525 530 535 tct att cag acg ctggta tgg ggg ctc gga ccc ctc act ggg gac agg 1862 Ser Ile Gln Thr Leu ValTrp Gly Leu Gly Pro Leu Thr Gly Asp Arg 540 545 550 555 gcc agt gtt ggagaa ttc tga ttcctttttt gttgtctttt acttttgttt 1913 Ala Ser Val Gly GluPhe * 560 ttaacctggg ggttcgggga gaggccctgc ttgggaacat ctcacgagctttcctacatc 1973 ttccgtggtt cccagcacag cccaagatta tttggcagcc aagtggatggaactaacttt 2033 cctggactgt gtttcgcatt cggcgttatc tggaaagtgg actgaacggaatcaagctct 2093 gagcagaggc ctgaagcgga agcaccacat cgtccctgcc catctcactctctcccttga 2153 tgatgcccct agagctgagg ctggagaaga caccagggct gactttgaccgagggccatg 2213 gacgcgacag gcctgtggcc ctgcgcatgc tgaaataact ggaacccagcctctcctcct 2273 acaccggcct acccatctgg gcccaagagc tgcactcaca ctcctacaacgaaggacaaa 2333 ctgtccaggt cggagggatc acgagacaca gaacctggag gggtgtgcacgctggcaggt 2393 ggcctctgcg gcaattgcct caccctgagg acatcagcag tcagcctgcttcagaagcgg 2453 nggtgctgga gcgccgtgca gacacaagct ttttcggagc aggccttcaccttctctntg 2513 ggatcaagtg tcccggctgg cccgacgtgg catttgctga cccgaatgcttatagaggtt 2573 gacccccaac agggtcaccg cangactcgg gacactgccc tggaaaacatggatggacaa 2633 ggggcttttg gccacaggtg tgggtgtcct gttggaggan ggctttgtttggagaangga 2693 ggcttgctgg gggagaaa 2711 42 561 PRT Homo sapiens 42 MetGlu Gly Gly Pro Ala Val Cys Cys Gln Asp Pro Arg Ala Glu Leu 1 5 10 15Val Glu Arg Val Ala Ala Ile Asp Val Thr His Leu Glu Glu Ala Asp 20 25 30Gly Gly Pro Glu Pro Thr Arg Asn Gly Val Asp Pro Pro Pro Arg Ala 35 40 45Arg Ala Ala Ser Val Ile Pro Gly Ser Thr Ser Arg Leu Leu Pro Ala 50 55 60Arg Pro Ser Leu Ser Ala Arg Lys Leu Ser Leu Gln Glu Arg Pro Ala 65 70 7580 Gly Ser Tyr Leu Glu Ala Gln Ala Gly Pro Tyr Ala Thr Gly Pro Ala 85 9095 Ser His Ile Ser Pro Arg Ala Trp Arg Arg Pro Thr Ile Glu Ser His 100105 110 His Val Ala Ile Ser Asp Ala Glu Asp Cys Val Gln Leu Asn Gln Tyr115 120 125 Lys Leu Gln Ser Glu Ile Gly Lys Gly Ala Tyr Gly Val Val ArgLeu 130 135 140 Ala Tyr Asn Glu Ser Glu Asp Arg His Tyr Ala Met Lys ValLeu Ser 145 150 155 160 Lys Lys Lys Leu Leu Lys Gln Tyr Gly Phe Pro ArgArg Pro Pro Pro 165 170 175 Arg Gly Ser Gln Ala Ala Gln Gly Gly Pro AlaLys Gln Leu Leu Pro 180 185 190 Leu Glu Arg Val Tyr Gln Glu Ile Ala IleLeu Lys Lys Leu Asp His 195 200 205 Val Asn Val Val Lys Leu Ile Glu ValLeu Asp Asp Pro Ala Glu Asp 210 215 220 Asn Leu Tyr Leu Val Phe Asp LeuLeu Arg Lys Gly Pro Val Met Glu 225 230 235 240 Val Pro Cys Asp Lys ProPhe Ser Glu Glu Gln Ala Arg Leu Tyr Leu 245 250 255 Arg Asp Val Ile LeuGly Leu Glu Tyr Leu His Cys Gln Lys Ile Val 260 265 270 His Arg Asp IleLys Pro Ser Asn Leu Leu Leu Gly Asp Asp Gly His 275 280 285 Val Lys IleAla Asp Phe Gly Val Ser Asn Gln Phe Glu Gly Asn Asp 290 295 300 Ala GlnLeu Ser Ser Thr Ala Gly Thr Pro Ala Phe Met Ala Pro Glu 305 310 315 320Ala Ile Ser Asp Ser Gly Gln Ser Phe Ser Gly Lys Ala Leu Asp Val 325 330335 Trp Ala Thr Gly Val Thr Leu Tyr Cys Phe Val Tyr Gly Lys Cys Pro 340345 350 Phe Ile Asp Asp Phe Ile Leu Ala Leu His Arg Lys Ile Lys Asn Glu355 360 365 Pro Val Val Phe Pro Glu Gly Pro Glu Ile Ser Glu Glu Leu LysAsp 370 375 380 Leu Ile Leu Lys Met Leu Asp Lys Asn Pro Glu Thr Arg IleGly Val 385 390 395 400 Pro Asp Ile Lys Leu His Pro Trp Val Thr Lys AsnGly Glu Glu Pro 405 410 415 Leu Pro Ser Glu Glu Glu His Cys Ser Val ValGlu Val Thr Glu Glu 420 425 430 Glu Val Lys Asn Ser Val Arg Leu Ile ProSer Trp Thr Thr Val Ile 435 440 445 Leu Val Lys Ser Met Leu Arg Lys ArgSer Phe Gly Asn Pro Phe Glu 450 455 460 Pro Gln Ala Arg Arg Glu Glu ArgSer Met Ser Ala Pro Gly Asn Leu 465 470 475 480 Leu Val Lys Glu Gly PheGly Glu Gly Gly Lys Ser Pro Glu Leu Pro 485 490 495 Gly Val Gln Ala TyrHis Asn Gly Arg Asp Leu Pro Leu Gly Pro Gly 500 505 510 Arg Pro Gly SerAla Ala Thr Gly Ile Trp Trp Arg Gly Gly Tyr Pro 515 520 525 Ala His LeuGly Val Val Ala Pro Glu Leu Leu Ser Ile Gln Thr Leu 530 535 540 Val TrpGly Leu Gly Pro Leu Thr Gly Asp Arg Ala Ser Val Gly Glu 545 550 555 560Phe 43 1686 DNA Homo sapiens CDS (1)...(1686) 43 atg gag ggg ggt cca gctgtc tgc tgc cag gat cct cgg gca gag ctg 48 Met Glu Gly Gly Pro Ala ValCys Cys Gln Asp Pro Arg Ala Glu Leu 1 5 10 15 gta gaa cgg gtg gca gccatc gat gtg act cac ttg gag gag gca gat 96 Val Glu Arg Val Ala Ala IleAsp Val Thr His Leu Glu Glu Ala Asp 20 25 30 ggt ggc cca gag cct act agaaac ggt gtg gac ccc cca cca cgg gcc 144 Gly Gly Pro Glu Pro Thr Arg AsnGly Val Asp Pro Pro Pro Arg Ala 35 40 45 aga gct gcc tct gtg atc cct ggcagt act tca aga ctg ctc cca gcc 192 Arg Ala Ala Ser Val Ile Pro Gly SerThr Ser Arg Leu Leu Pro Ala 50 55 60 cgg cct agc ctc tca gcc agg aag ctttcc cta cag gag cgg cca gca 240 Arg Pro Ser Leu Ser Ala Arg Lys Leu SerLeu Gln Glu Arg Pro Ala 65 70 75 80 gga agc tat ctg gag gcg cag gct gggcct tat gcc acg ggg cct gcc 288 Gly Ser Tyr Leu Glu Ala Gln Ala Gly ProTyr Ala Thr Gly Pro Ala 85 90 95 agc cac atc tcc ccc cgg gcc tgg cgg aggccc acc atc gag tcc cac 336 Ser His Ile Ser Pro Arg Ala Trp Arg Arg ProThr Ile Glu Ser His 100 105 110 cac gtg gcc atc tca gat gca gag gac tgcgtg cag ctg aac cag tac 384 His Val Ala Ile Ser Asp Ala Glu Asp Cys ValGln Leu Asn Gln Tyr 115 120 125 aag ctg cag agt gag att ggc aag ggt gcctac ggt gtg gtg agg ctg 432 Lys Leu Gln Ser Glu Ile Gly Lys Gly Ala TyrGly Val Val Arg Leu 130 135 140 gcc tac aac gaa agt gaa gac aga cac tatgca atg aaa gtc ctt tcc 480 Ala Tyr Asn Glu Ser Glu Asp Arg His Tyr AlaMet Lys Val Leu Ser 145 150 155 160 aaa aag aag tta ctg aag cag tat ggcttt cca cgt cgc cct ccc cca 528 Lys Lys Lys Leu Leu Lys Gln Tyr Gly PhePro Arg Arg Pro Pro Pro 165 170 175 aga ggg tcc cag gct gcc cag gga ggacca gcc aag cag ctg ctg ccc 576 Arg Gly Ser Gln Ala Ala Gln Gly Gly ProAla Lys Gln Leu Leu Pro 180 185 190 ctg gag cgg gtg tac cag gag att gccatc ctg aag aag ctg gac cac 624 Leu Glu Arg Val Tyr Gln Glu Ile Ala IleLeu Lys Lys Leu Asp His 195 200 205 gtg aat gtg gtc aaa ctg atc gag gtcctg gat gac cca gct gag gac 672 Val Asn Val Val Lys Leu Ile Glu Val LeuAsp Asp Pro Ala Glu Asp 210 215 220 aac ctc tat ttg gtg ttt gac ctc ctgaga aag ggg ccc gtc atg gaa 720 Asn Leu Tyr Leu Val Phe Asp Leu Leu ArgLys Gly Pro Val Met Glu 225 230 235 240 gtg ccc tgt gac aag ccc ttc tcggag gag caa gct cgc ctc tac ctg 768 Val Pro Cys Asp Lys Pro Phe Ser GluGlu Gln Ala Arg Leu Tyr Leu 245 250 255 cgg gac gtc atc ctg ggc ctc gagtac ttg cac tgc cag aag atc gtc 816 Arg Asp Val Ile Leu Gly Leu Glu TyrLeu His Cys Gln Lys Ile Val 260 265 270 cac agg gac atc aag cca tcc aacctg ctc ctg ggg gat gat ggg cac 864 His Arg Asp Ile Lys Pro Ser Asn LeuLeu Leu Gly Asp Asp Gly His 275 280 285 gtg aag atc gcc gac ttt ggc gtcagc aac cag ttt gag ggg aac gac 912 Val Lys Ile Ala Asp Phe Gly Val SerAsn Gln Phe Glu Gly Asn Asp 290 295 300 gct cag ctg tcc agc acg gcg ggaacc cca gca ttc atg gcc ccc gag 960 Ala Gln Leu Ser Ser Thr Ala Gly ThrPro Ala Phe Met Ala Pro Glu 305 310 315 320 gcc att tct gat tcc ggc cagagc ttc agt ggg aag gcc ttg gat gta 1008 Ala Ile Ser Asp Ser Gly Gln SerPhe Ser Gly Lys Ala Leu Asp Val 325 330 335 tgg gcc act ggc gtc acg ttgtac tgc ttt gtc tat ggg aag tgc ccg 1056 Trp Ala Thr Gly Val Thr Leu TyrCys Phe Val Tyr Gly Lys Cys Pro 340 345 350 ttc atc gac gat ttc atc ctggcc ctc cac agg aag atc aag aat gag 1104 Phe Ile Asp Asp Phe Ile Leu AlaLeu His Arg Lys Ile Lys Asn Glu 355 360 365 ccc gtg gtg ttt cct gag gggcca gaa atc agc gag gag ctc aag gac 1152 Pro Val Val Phe Pro Glu Gly ProGlu Ile Ser Glu Glu Leu Lys Asp 370 375 380 ctg atc ctg aag atg tta gacaag aat ccc gag acg aga att ggg gtg 1200 Leu Ile Leu Lys Met Leu Asp LysAsn Pro Glu Thr Arg Ile Gly Val 385 390 395 400 cca gac atc aag ttg caccct tgg gtg acc aag aac ggg gag gag ccc 1248 Pro Asp Ile Lys Leu His ProTrp Val Thr Lys Asn Gly Glu Glu Pro 405 410 415 ctt cct tcg gag gag gagcac tgc agc gtg gtg gag gtg aca gag gag 1296 Leu Pro Ser Glu Glu Glu HisCys Ser Val Val Glu Val Thr Glu Glu 420 425 430 gag gtt aag aac tca gtcagg ctc atc ccc agc tgg acc acg gtg atc 1344 Glu Val Lys Asn Ser Val ArgLeu Ile Pro Ser Trp Thr Thr Val Ile 435 440 445 ctg gtg aag tcc atg ctgagg aag cgt tcc ttt ggg aac ccg ttt gag 1392 Leu Val Lys Ser Met Leu ArgLys Arg Ser Phe Gly Asn Pro Phe Glu 450 455 460 ccc caa gca cgg agg gaagag cga tcc atg tct gct cca gga aac cta 1440 Pro Gln Ala Arg Arg Glu GluArg Ser Met Ser Ala Pro Gly Asn Leu 465 470 475 480 ctg gtg aaa gaa gggttt ggt gaa ggg ggc aag agc cca gag ctc ccc 1488 Leu Val Lys Glu Gly PheGly Glu Gly Gly Lys Ser Pro Glu Leu Pro 485 490 495 ggc gtc cag gct taccac aac gga aga gac ctc ccg ctg ggg ccg ggc 1536 Gly Val Gln Ala Tyr HisAsn Gly Arg Asp Leu Pro Leu Gly Pro Gly 500 505 510 agg cct ggc tca gctgcc aca ggc ata tgg tgg aga ggg ggg tac cct 1584 Arg Pro Gly Ser Ala AlaThr Gly Ile Trp Trp Arg Gly Gly Tyr Pro 515 520 525 gcc cac ctt ggg gtggtg gca cca gag ctc ttg tct att cag acg ctg 1632 Ala His Leu Gly Val ValAla Pro Glu Leu Leu Ser Ile Gln Thr Leu 530 535 540 gta tgg ggg ctc ggaccc ctc act ggg gac agg gcc agt gtt gga gaa 1680 Val Trp Gly Leu Gly ProLeu Thr Gly Asp Arg Ala Ser Val Gly Glu 545 550 555 560 ttc tga 1686Phe * 44 178 PRT Artificial Sequence Consensus amino acid sequence 44Glu Val Thr Leu Leu Asp Thr Lys Thr Ala Thr Gly Glu Leu Gly Trp 1 5 1015 Leu Thr Tyr Pro Val Pro Ser Gly Trp Glu Glu Val Ser Gly Leu Asp 20 2530 Glu Asn Asn Arg Pro Ile Arg Thr Tyr Gln Val Cys Asn Val Met Glu 35 4045 Pro Asn Gln Asn Asn Trp Leu Arg Thr Asn Trp Ile Glu Arg Arg Gly 50 5560 Ala Gln Arg Val Tyr Val Glu Leu Lys Phe Thr Val Arg Asp Cys Asn 65 7075 80 Ser Leu Pro Gly Val Leu Gly Thr Cys Lys Glu Thr Phe Asn Leu Tyr 8590 95 Tyr Tyr Glu Ser Asp Glu Asp Val Gly Thr Ala Leu Pro Ala Trp Arg100 105 110 Glu Asn Gln Tyr Ile Lys Val Asp Thr Ile Ala Ala Asp Glu SerPhe 115 120 125 Thr Gln Val Asp Leu Gly Asp Arg Val Leu Lys Leu Asn ThrGlu Val 130 135 140 Arg Ser Val Gly Pro Leu Ser Lys Lys Gly Phe Tyr LeuAla Phe Gln 145 150 155 160 Asp Val Gly Ala Cys Ile Ala Leu Val Ser ValArg Val Phe Tyr Lys 165 170 175 Lys Cys 45 273 PRT Artificial SequenceConsensus amino acid sequence 45 Tyr Glu Leu Leu Glu Lys Leu Gly Glu GlySer Phe Gly Lys Val Tyr 1 5 10 15 Lys Ala Lys His Lys Thr Gly Lys IleVal Ala Val Lys Ile Leu Lys 20 25 30 Lys Glu Ser Leu Ser Leu Arg Glu IleGln Ile Leu Lys Arg Leu Ser 35 40 45 His Pro Asn Ile Val Arg Leu Leu GlyVal Phe Glu Asp Thr Asp Asp 50 55 60 His Leu Tyr Leu Val Met Glu Tyr MetGlu Gly Gly Asp Leu Phe Asp 65 70 75 80 Tyr Leu Arg Arg Asn Gly Pro LeuSer Glu Lys Glu Ala Lys Lys Ile 85 90 95 Ala Leu Gln Ile Leu Arg Gly LeuGlu Tyr Leu His Ser Asn Gly Ile 100 105 110 Val His Arg Asp Leu Lys ProGlu Asn Ile Leu Leu Asp Glu Asn Gly 115 120 125 Thr Val Lys Ile Ala AspPhe Gly Leu Ala Arg Leu Leu Glu Lys Leu 130 135 140 Thr Thr Phe Val GlyThr Pro Trp Tyr Met Met Ala Pro Glu Val Ile 145 150 155 160 Leu Glu GlyArg Gly Tyr Ser Ser Lys Val Asp Val Trp Ser Leu Gly 165 170 175 Val IleLeu Tyr Glu Leu Leu Thr Gly Gly Pro Leu Phe Pro Gly Ala 180 185 190 AspLeu Pro Ala Phe Thr Gly Gly Asp Glu Val Asp Gln Leu Ile Ile 195 200 205Phe Val Leu Lys Leu Pro Phe Ser Asp Glu Leu Pro Lys Thr Arg Ile 210 215220 Asp Pro Leu Glu Glu Leu Phe Arg Ile Lys Lys Arg Arg Leu Pro Leu 225230 235 240 Pro Ser Asn Cys Ser Glu Glu Leu Lys Asp Leu Leu Lys Lys CysLeu 245 250 255 Asn Lys Asp Pro Ser Lys Arg Pro Gly Ser Ala Thr Ala LysGlu Ile 260 265 270 Leu 46 180 PRT Artificial Sequence Consensus aminoacid sequence 46 Glu Val Thr Leu Leu Asp Thr Lys Thr Val Gln Gly Glu LeuGly Trp 1 5 10 15 Ile Thr Tyr Pro Pro Gln Asn Gly Gly Trp Glu Glu ValSer Gly Met 20 25 30 Asp Glu Asn Asn Thr Pro Ile Arg Thr Tyr Gln Val CysAsn Val Met 35 40 45 Glu Pro His Asn Gln Asn Asn Trp Leu Arg Thr Asn TrpIle Pro Arg 50 55 60 Arg Gly Ala Gln Arg Ile Tyr Val Glu Leu Lys Phe ThrVal Arg Asp 65 70 75 80 Cys Asn Ser Leu Pro Gly Val Ala Gly Thr Cys LysGlu Thr Phe Asn 85 90 95 Leu Tyr Tyr Tyr Glu Ser Asp Glu Asp Thr Gly ThrAla Thr Ser Pro 100 105 110 Asn Trp Arg Glu Asn Gln Tyr Val Lys Ile AspThr Ile Ala Ala Asp 115 120 125 Glu Ser Phe Thr Gln Met Asp Leu Gly AspArg Val Met Lys Leu Asn 130 135 140 Thr Glu Val Arg Ser Ile Gly Pro LeuSer Lys Lys Gly Phe Tyr Leu 145 150 155 160 Ala Phe Gln Asp Val Gly AlaCys Ile Ala Leu Ile Ser Val Arg Val 165 170 175 Tyr Tyr Lys Lys 180 47127 PRT Artificial Sequence Consensus amino acid sequence 47 Tyr Arg AlaPro Ser Asp Pro Pro Ser Met Pro Cys Thr Arg Pro Pro 1 5 10 15 Ser AlaPro Arg Asn Leu Ile Ser Asn Phe Val Asn Glu Thr Ser Val 20 25 30 Met LeuGlu Trp Ser Pro Pro Ala Asp Thr Gly Gly Arg Ser Asp Ile 35 40 45 Thr TyrAsn Val Ile Cys Lys Lys Cys Arg Ser Trp Gly Asp Lys Gly 50 55 60 Lys CysAsn Pro Cys Gly Asp Asn Val His Phe Ser Pro Arg Gln Thr 65 70 75 80 GlyLeu Thr Glu Thr Arg Val Thr Val Thr Asp Leu Glu Pro His Thr 85 90 95 AsnTyr Thr Phe Glu Val Glu Ala Val Asn Gly Val Ser Asp Leu Ser 100 105 110Pro Ser Pro Pro Gln Tyr Ala Ser Val Asn Val Thr Thr Asn Gln 115 120 12548 50 PRT Artificial Sequence Consensus amino acid sequence 48 Glu GlyVal Val Thr Lys Arg Ser Phe Pro Ala Ile Gly Val Glu Ala 1 5 10 15 PheCys Pro Ser Phe Leu Arg Ala Gly Phe Leu Asn Gly Ile Gln Ala 20 25 30 ProHis Pro Val Pro Gly Gly Gly Ser Leu Pro Pro Arg Ile Pro Ala 35 40 45 GlyArg 50 49 59 PRT Artificial Sequence Consensus amino acid sequence 49Leu Gly Lys Cys Lys Cys Lys Ala Gly Tyr Glu Pro Asn Glu Asn Asn 1 5 1015 Lys Thr Cys Gln Ala Cys Pro Pro Gly Thr Tyr Lys Ala Glu Ala Gly 20 2530 Asp Ser Ser Cys Ser Pro Cys Pro Pro His Ser Thr Thr Thr Ser Glu 35 4045 Gly Ser Thr Thr Cys Thr Cys Glu Cys Gly Tyr 50 55 50 178 PRTArtificial Sequence Consensus amino acid sequence 50 Met Val Gln Glu TyrVal Arg Tyr Gly Pro Leu Asp Leu Phe Leu His 1 5 10 15 Lys Asn Lys ProAsn Val Thr Leu His Trp Lys Leu Asp Val Ala Lys 20 25 30 Gln Leu Ala ArgAla Met His Tyr Leu Glu Asp Lys Lys Leu Val His 35 40 45 Gly Asn Val CysCys Lys Asn Ile Leu Val Thr Arg Glu Gly Pro Glu 50 55 60 Lys Asn Ser TyrPro Pro Phe Ile Lys Leu Ser Asp Pro Gly Ile Pro 65 70 75 80 Ile Thr ValLeu Thr Arg Glu Tyr Arg Val Glu Arg Ile Pro Trp Ile 85 90 95 Pro Pro GluCys Ile Glu Asn Pro Gln Asn Leu Lys Thr Asp Gln Phe 100 105 110 Ala AspLys Trp Ser Phe Gly Thr Thr Leu Trp Glu Ile Cys Ser Asn 115 120 125 GlyGlu Glu Pro Leu Ser Thr Leu Arg Gln Glu Glu Leu Lys Glu Arg 130 135 140Phe Tyr Glu Asp Arg His Gln Leu Pro Ala Pro Lys Trp Lys Glu Leu 145 150155 160 Ala Asn Leu Ile Asn His Cys Met Asp Tyr Asp Pro Thr Gln Arg Pro165 170 175 Phe Phe 51 55 PRT Artificial Sequence Consensus amino acidsequence 51 Arg Arg Lys Gly Tyr Ser Lys Ala Glu Gln Glu Tyr Asp Glu LysLys 1 5 10 15 Gln His Tyr His Asn Gly His Leu Lys Ala Pro Gly Val LysThr Tyr 20 25 30 Ile Asp Pro Phe Thr Tyr Glu Asp Pro Asn Gln Ala Val ArgGlu Phe 35 40 45 Ala Lys Glu Ile Asp Val Ser 50 55 52 278 PRT ArtificialSequence Consensus amino acid sequence 52 Tyr Glu Leu Leu Glu Lys LeuGly Glu Gly Ser Phe Gly Lys Val Tyr 1 5 10 15 Lys Ala Lys His Lys ThrGly Lys Ile Val Ala Val Lys Ile Leu Lys 20 25 30 Lys Glu Ser Leu Ser LeuArg Glu Ile Gln Ile Leu Lys Arg Leu Ser 35 40 45 His Pro Asn Ile Val ArgLeu Leu Gly Val Phe Glu Asp Thr Asp Asp 50 55 60 His Leu Tyr Leu Val MetGlu Tyr Met Glu Gly Gly Asp Leu Phe Asp 65 70 75 80 Tyr Leu Arg Arg AsnGly Pro Leu Ser Glu Lys Glu Ala Lys Lys Ile 85 90 95 Ala Leu Gln Ile LeuArg Gly Leu Glu Tyr Leu His Ser Asn Gly Ile 100 105 110 Val His Arg AspLeu Lys Pro Glu Asn Ile Leu Leu Asp Glu Asn Gly 115 120 125 Thr Val LysIle Ala Asp Phe Gly Leu Ala Arg Leu Leu Glu Lys Leu 130 135 140 Thr ThrPhe Val Gly Thr Pro Trp Tyr Met Met Ala Pro Glu Val Ile 145 150 155 160Leu Glu Gly Arg Gly Tyr Ser Ser Lys Val Asp Val Trp Ser Leu Gly 165 170175 Val Ile Leu Tyr Glu Leu Leu Thr Gly Gly Pro Leu Phe Pro Gly Ala 180185 190 Asp Leu Pro Ala Phe Thr Gly Gly Asp Glu Val Asp Gln Leu Ile Ile195 200 205 Phe Val Leu Lys Leu Pro Phe Ser Asp Glu Leu Pro Lys Thr ArgIle 210 215 220 Asp Pro Leu Glu Glu Leu Phe Arg Ile Lys Lys Arg Arg LeuPro Leu 225 230 235 240 Pro Ser Asn Cys Ser Glu Glu Leu Lys Asp Leu LeuLys Lys Cys Leu 245 250 255 Asn Lys Asp Pro Ser Lys Arg Pro Gly Ser AlaThr Ala Lys Glu Ile 260 265 270 Leu Asn His Pro Trp Phe 275 53 48 PRTArtificial Sequence Consensus amino acid sequence 53 Gly Thr Arg Trp TyrMet Ala Pro Glu Val Leu Met Gly Ser Ser Tyr 1 5 10 15 Gly Gln Tyr SerGlu Lys Ser Asp Val Trp Ser Phe Gly Val Ile Leu 20 25 30 Tyr Glu Leu LeuThr Gly Lys Pro Pro Phe Phe Pro Gly Ser Ser Glu 35 40 45 54 100 PRTArtificial Sequence Consensus amino acid sequence 54 Glu Met Met Glu LysLeu Gln Lys Gln Ser Met Ser Glu Lys Lys Met 1 5 10 15 Glu Glu Met SerTrp Val Ser Gln Leu Met Lys Ile Ala Tyr Gln Ile 20 25 30 Ala Lys Gly LeuGlu Tyr Leu His Ser Lys Ser Asn Lys Gln Asn Ile 35 40 45 Ile His Arg AspLeu Lys Pro Glu Asn Ile Leu Leu Asp Asn Asn Met 50 55 60 Val Ala Lys GlyAsp Ser Glu Ile Lys Val Val Lys Ile Ala Asp Phe 65 70 75 80 Gly Leu AlaArg Met Ile Glu Glu Ser Ser Glu Glu Ser Ser Ser Ser 85 90 95 Ser Ser SerThr 100 55 134 PRT Artificial Sequence Consensus amino acid sequence 55Lys Ala Ala Thr Lys Val Ala Val Lys Lys Lys Met Lys Glu Glu Glu 1 5 1015 Lys Lys Glu Ser Lys Thr Ser Met Arg Glu Glu Glu Met Gln Met Met 20 2530 Met Glu Ile Glu Thr His Pro Asn Ile Met Ile Ile Arg His Val Asn 35 4045 Leu Val Val Val Met Gly Tyr Cys Thr Tyr Glu Glu Ser Glu Glu Glu 50 5560 Asp Glu Asn Lys Leu Tyr Ile Val Met Glu Tyr Met Asn Gly Gly Ser 65 7075 80 Leu Glu Asp Tyr Leu Glu Met Met Glu Lys Leu Gln Lys Gln Ser Met 8590 95 Ser Glu Lys Lys Met Glu Glu Met Ser Trp Val Ser Gln Leu Met Lys100 105 110 Ile Ala Tyr Gln Ile Ala Lys Gly Leu Glu Tyr Leu His Ser LysSer 115 120 125 Asn Lys Gln Asn Ile Ile 130 56 40 PRT ArtificialSequence Consensus amino acid sequence 56 Glu Glu Leu Ser Ala His GluIle Lys Gln His Pro Trp Phe Arg Lys 1 5 10 15 Arg Asp Ser Phe Ser AspMet His Ser Val Gly Tyr Met Met Tyr Glu 20 25 30 Met Met Ser Gly Gln ProPro Phe 35 40 57 80 PRT Artificial Sequence Consensus amino acidsequence 57 Tyr Glu Leu Leu Lys Lys Leu Gly Glu Gly Ser Phe Gly Lys ValTyr 1 5 10 15 Lys Ala Arg His Lys Val Val Tyr Lys Ala Lys Asp Lys SerLys Glu 20 25 30 Thr Tyr Ala Ala Lys Val Val Ala Lys Leu Lys Val Leu LysAla Ala 35 40 45 Thr Lys Val Ala Val Lys Lys Lys Met Lys Glu Glu Glu LysLys Glu 50 55 60 Ser Lys Thr Ser Met Arg Glu Glu Glu Met Gln Met Met MetGlu Ile 65 70 75 80 58 27 PRT Artificial Sequence Consensus amino acidsequence 58 Ser Glu Ala Val Lys Asp Leu Ile Lys Lys Cys Trp Gln Lys AspPro 1 5 10 15 Glu Lys Arg Pro Thr Phe Ala Gln Val Val Glu 20 25 59 162PRT Artificial Sequence Consensus amino acid sequence 59 Ser Leu Gly ValCys Ile Phe Val Met Ala Thr Gly Ser Cys Pro Phe 1 5 10 15 Ile Leu GluSer Arg Asn Thr Met Met Glu Ser Ile Gln Ala Gly Ile 20 25 30 Leu Gly SerPro Val Leu Ala Ser Asp Lys Ile Gln Ser Leu Val Glu 35 40 45 Gln Leu IleHis Val Asn Pro Ser Glu Arg Met Ser Leu Lys Ser Leu 50 55 60 Ile Glu AspAsp Trp Met Thr Ser Asp Leu Val Trp Asn Tyr Phe Ile 65 70 75 80 Ser CysHis Glu Asp Leu Ile Arg Glu Leu Pro Val Val Asp Arg Phe 85 90 95 Ile ProAla Glu Ser Leu Glu Lys Ser Thr Val Gln Arg Asp Gly Ser 100 105 110 GluIle Ser Ile Glu Thr Leu Asp Glu Gly Tyr Lys Ser Val Ala Ser 115 120 125Asp His Pro Glu Glu Pro Ala Val Ser Gly Glu Gln Gln Val Leu Thr 130 135140 Glu Pro Val Pro Lys Lys Tyr His Lys Lys Phe Ala Val Phe Ala Met 145150 155 160 Glu Asn 60 141 PRT Artificial Sequence Consensus amino acidsequence 60 Ile Ala Ser Gly Arg Phe Gly Thr Val Phe Leu Gly Thr Ile ThrAsp 1 5 10 15 Ser Met Leu Gln Val Ala Ile Lys Glu Tyr His Glu Thr PheHis Asp 20 25 30 Ala Val Leu Thr Ala His Asp Glu Gly Ser Thr Leu Gln LysIle Ile 35 40 45 Ser Ile Glu His Pro Ala Ile Val Gln Thr Phe Ser Val SerHis Phe 50 55 60 Gln Asp Ile Val Tyr Lys Val Met Glu Phe His Ser Trp ThrLeu His 65 70 75 80 Glu Lys Arg Val Tyr Phe Glu Lys Ile Asp Arg Thr AsnAsn Asp Ile 85 90 95 Leu Asp Lys Gly Lys Tyr Asp Glu Ser Gln Thr Lys LeuVal Leu Val 100 105 110 Gln Ala Thr Arg Ala Leu Glu Tyr Leu His Ala GlnAsn Leu Cys His 115 120 125 Gly Thr Leu His Thr Lys Asn Ile Phe Leu GlnGlu Asn 130 135 140 61 278 PRT Artificial Sequence Consensus amino acidsequence 61 Tyr Glu Leu Leu Glu Lys Leu Gly Glu Gly Ser Phe Gly Lys ValTyr 1 5 10 15 Lys Ala Lys His Lys Thr Gly Lys Ile Val Ala Val Lys IleLeu Lys 20 25 30 Lys Glu Ser Leu Ser Leu Arg Glu Ile Gln Ile Leu Lys ArgLeu Ser 35 40 45 His Pro Asn Ile Val Arg Leu Leu Gly Val Phe Glu Asp ThrAsp Asp 50 55 60 His Leu Tyr Leu Val Met Glu Tyr Met Glu Gly Gly Asp LeuPhe Asp 65 70 75 80 Tyr Leu Arg Arg Asn Gly Pro Leu Ser Glu Lys Glu AlaLys Lys Ile 85 90 95 Ala Leu Gln Ile Leu Arg Gly Leu Glu Tyr Leu His SerAsn Gly Ile 100 105 110 Val His Arg Asp Leu Lys Pro Glu Asn Ile Leu LeuAsp Glu Asn Gly 115 120 125 Thr Val Lys Ile Ala Asp Phe Gly Leu Ala ArgLeu Leu Glu Lys Leu 130 135 140 Thr Thr Phe Val Gly Thr Pro Trp Tyr MetMet Ala Pro Glu Val Ile 145 150 155 160 Leu Glu Gly Arg Gly Tyr Ser SerLys Val Asp Val Trp Ser Leu Gly 165 170 175 Val Ile Leu Tyr Glu Leu LeuThr Gly Gly Pro Leu Phe Pro Gly Ala 180 185 190 Asp Leu Pro Ala Phe ThrGly Gly Asp Glu Val Asp Gln Leu Ile Ile 195 200 205 Phe Val Leu Lys LeuPro Phe Ser Asp Glu Leu Pro Lys Thr Arg Ile 210 215 220 Asp Pro Leu GluGlu Leu Phe Arg Ile Lys Lys Arg Arg Leu Pro Leu 225 230 235 240 Pro SerAsn Cys Ser Glu Glu Leu Lys Asp Leu Leu Lys Lys Cys Leu 245 250 255 AsnLys Asp Pro Ser Lys Arg Pro Gly Ser Ala Thr Ala Lys Glu Ile 260 265 270Leu Asn His Pro Trp Phe 275 62 80 PRT Artificial Sequence Consensusamino acid sequence 62 Met Glu Arg Ser Pro Ala Val Cys Cys Gln Asp ProArg Ala Glu Leu 1 5 10 15 Val Glu Arg Val Ala Ala Ile Ser Val Ala HisLeu Glu Glu Ala Glu 20 25 30 Glu Gly Pro Glu Pro Ala Ser Asn Gly Val AspPro Pro Pro Arg Ala 35 40 45 Arg Ala Ala Ser Val Ile Pro Gly Ser Ala SerArg Pro Thr Pro Val 50 55 60 Arg Pro Ser Leu Ser Ala Arg Lys Phe Ser LeuGln Glu Arg Pro Ala 65 70 75 80 63 61 PRT Artificial Sequence Consensusamino acid sequence 63 Leu Lys Thr His Lys Trp Val Thr Arg His Gly GluGlu Pro Leu Pro 1 5 10 15 Ser Glu Glu Glu Asn Cys Thr Leu Val Glu ValThr Glu Glu Glu Val 20 25 30 Glu Asn Ser Val Lys His Ile Pro Ser Leu ThrThr Val Ile Leu Val 35 40 45 Lys Thr Met Leu Arg Lys Arg Ser Phe Gly AsnPro Phe 50 55 60 64 47 PRT Artificial Sequence Consensus amino acidsequence 64 Gly Xaa Cys Leu Gly Ala Gln Val Gly Pro Tyr Ser Thr Gly ProAla 1 5 10 15 Ser His Met Cys Pro Arg Ser Trp Arg Arg Pro Thr Ile GluSer His 20 25 30 Arg Val Ala Ile Ser Asp Thr Glu Asp Cys Val Gln Leu AsnGln 35 40 45 65 36 PRT Artificial Sequence Consensus amino acid sequence65 Glu Pro Gln Ala Arg Arg Glu Glu Arg Ser Met Ser Ala Pro Gly Asn 1 510 15 Leu Leu Leu Lys Glu Gly Cys Gly Glu Gly Gly Lys Ser Pro Glu Leu 2025 30 Pro Gly Val Gln 35 66 17 PRT Artificial Sequence Consensus aminoacid sequence 66 Xaa Gly Xaa Gly Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa XaaXaa Xaa 1 5 10 15 Lys 67 13 PRT Artificial Sequence Consensus amino acidsequence 67 Xaa Xaa Xaa Xaa Asp Xaa Xaa Xaa Xaa Asn Xaa Xaa Xaa 1 5 1068 13 PRT Artificial Sequence Consensus amino acid sequence 68 Xaa XaaXaa Xaa Asp Xaa Lys Xaa Xaa Asn Xaa Xaa Xaa 1 5 10 69 21 PRT ArtificialSequence Consensus amino acid sequence 69 Phe Xaa Xaa Xaa Xaa Xaa CysXaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 1 5 10 15 Xaa Xaa Xaa Cys Xaa 20 7020 PRT Artificial Sequence Consensus amino acid sequence 70 Cys Xaa XaaXaa Gly Xaa Trp Xaa Xaa Xaa Xaa Xaa Cys Xaa Cys Xaa 1 5 10 15 Xaa GlyXaa Xaa 20 71 9 PRT Artificial Sequence Consensus amino acid sequence 71Cys Xaa Cys Xaa Xaa Xaa Xaa Xaa Cys 1 5 72 8 PRT Artificial SequenceConsensus amino acid sequence 72 Xaa Xaa Xaa Xaa Xaa Gly Lys Xaa 1 5 731154 DNA Homo sapiens CDS (22)...(870) 73 cggacgcgtg ggtccgtgac c atgaag gtc aag gtc atc ccc gtg ctc gag 51 Met Lys Val Lys Val Ile Pro ValLeu Glu 1 5 10 gac aac tac atg tac ctg gtc atc gag gag ctc acg cgc gaggcg gtg 99 Asp Asn Tyr Met Tyr Leu Val Ile Glu Glu Leu Thr Arg Glu AlaVal 15 20 25 gcc gtg gac gtg gct gtg ccc aag agg ctg ctg gag atc gtg ggccgg 147 Ala Val Asp Val Ala Val Pro Lys Arg Leu Leu Glu Ile Val Gly Arg30 35 40 gag ggg gtg tct ctg acc gct gtg ctg acc acc cac cat cac tgg gac195 Glu Gly Val Ser Leu Thr Ala Val Leu Thr Thr His His His Trp Asp 4550 55 cac gcg cgg gga aac ccg gag ctg gcg cgg ctt cgt ccc ggg ctg gcg243 His Ala Arg Gly Asn Pro Glu Leu Ala Arg Leu Arg Pro Gly Leu Ala 6065 70 gtg ctg ggc gcg gac gag cgc atc ttc tcg ctg acg cgc agg ctg gcg291 Val Leu Gly Ala Asp Glu Arg Ile Phe Ser Leu Thr Arg Arg Leu Ala 7580 85 90 cac ggc gag gag ctg cgg ttc ggg gcc atc cac gtg cgt tgc ctc ctg339 His Gly Glu Glu Leu Arg Phe Gly Ala Ile His Val Arg Cys Leu Leu 95100 105 acg ccc ggc cac acc gcc ggc cac atg agc tac ttc ctg tgg gag gac387 Thr Pro Gly His Thr Ala Gly His Met Ser Tyr Phe Leu Trp Glu Asp 110115 120 gat tgc ccg gac cca ccc gcc ctg ttc tcg ggc gac gcg ctg tcg gtg435 Asp Cys Pro Asp Pro Pro Ala Leu Phe Ser Gly Asp Ala Leu Ser Val 125130 135 gcc ggc tgc ggc tcg tgc ctg gag ggc agc gcc cag cag atg tac cag483 Ala Gly Cys Gly Ser Cys Leu Glu Gly Ser Ala Gln Gln Met Tyr Gln 140145 150 agc ctg gcc gag ctg ggt acc ctg ccc ccc gag acg aag gtg ttc tgc531 Ser Leu Ala Glu Leu Gly Thr Leu Pro Pro Glu Thr Lys Val Phe Cys 155160 165 170 ggc cac gag cac acg ctt agc aac ctg gag ttt gcc cag aaa gtggag 579 Gly His Glu His Thr Leu Ser Asn Leu Glu Phe Ala Gln Lys Val Glu175 180 185 ccc tgc aac gac cac gtg aga gcc aag ctg tcc tgg gct aag aagagg 627 Pro Cys Asn Asp His Val Arg Ala Lys Leu Ser Trp Ala Lys Lys Arg190 195 200 gat gag gat gac gtg ccc act gtg ccg tcg act ctg ggc gag gagcgc 675 Asp Glu Asp Asp Val Pro Thr Val Pro Ser Thr Leu Gly Glu Glu Arg205 210 215 ctc tac aac ccc ttc ctg cgg gtg gca gag gag ccg gtg cgc aagttc 723 Leu Tyr Asn Pro Phe Leu Arg Val Ala Glu Glu Pro Val Arg Lys Phe220 225 230 acg ggc aag gcg gtc ccc gcc gac gtc ctg gag gcg cta tgc aaggag 771 Thr Gly Lys Ala Val Pro Ala Asp Val Leu Glu Ala Leu Cys Lys Glu235 240 245 250 cgg gcg cgc ttc gaa cag gcg ggc gag ccg cgg cag cca caggcg cgg 819 Arg Ala Arg Phe Glu Gln Ala Gly Glu Pro Arg Gln Pro Gln AlaArg 255 260 265 gcc ctc ctt gcg ctg cag tgg ggg ctc ctg agt gca gcc ccacac gac 867 Ala Leu Leu Ala Leu Gln Trp Gly Leu Leu Ser Ala Ala Pro HisAsp 270 275 280 tga gccacccaga ccctcacagg gctggggcct gcgtccctcctcgtgacctc 920 * ggccagctgg acccacatga gggccacctc tggaaccttc ttcgaggccctggccagcca 980 tctgcccagc ctcggagggt gggcaacctg gtgcttcccg ggtggacacacaggaccact 1040 cagtggggcc tgtgtgggcg ccgagacctg ggtgtctggg aagtggggcacacggggcct 1100 ccgaactatg aataaagctt tgaaagccgt tgtcaaaaaa aaaaaaaaaaaaaa 1154 74 282 PRT Homo sapiens 74 Met Lys Val Lys Val Ile Pro Val LeuGlu Asp Asn Tyr Met Tyr Leu 1 5 10 15 Val Ile Glu Glu Leu Thr Arg GluAla Val Ala Val Asp Val Ala Val 20 25 30 Pro Lys Arg Leu Leu Glu Ile ValGly Arg Glu Gly Val Ser Leu Thr 35 40 45 Ala Val Leu Thr Thr His His HisTrp Asp His Ala Arg Gly Asn Pro 50 55 60 Glu Leu Ala Arg Leu Arg Pro GlyLeu Ala Val Leu Gly Ala Asp Glu 65 70 75 80 Arg Ile Phe Ser Leu Thr ArgArg Leu Ala His Gly Glu Glu Leu Arg 85 90 95 Phe Gly Ala Ile His Val ArgCys Leu Leu Thr Pro Gly His Thr Ala 100 105 110 Gly His Met Ser Tyr PheLeu Trp Glu Asp Asp Cys Pro Asp Pro Pro 115 120 125 Ala Leu Phe Ser GlyAsp Ala Leu Ser Val Ala Gly Cys Gly Ser Cys 130 135 140 Leu Glu Gly SerAla Gln Gln Met Tyr Gln Ser Leu Ala Glu Leu Gly 145 150 155 160 Thr LeuPro Pro Glu Thr Lys Val Phe Cys Gly His Glu His Thr Leu 165 170 175 SerAsn Leu Glu Phe Ala Gln Lys Val Glu Pro Cys Asn Asp His Val 180 185 190Arg Ala Lys Leu Ser Trp Ala Lys Lys Arg Asp Glu Asp Asp Val Pro 195 200205 Thr Val Pro Ser Thr Leu Gly Glu Glu Arg Leu Tyr Asn Pro Phe Leu 210215 220 Arg Val Ala Glu Glu Pro Val Arg Lys Phe Thr Gly Lys Ala Val Pro225 230 235 240 Ala Asp Val Leu Glu Ala Leu Cys Lys Glu Arg Ala Arg PheGlu Gln 245 250 255 Ala Gly Glu Pro Arg Gln Pro Gln Ala Arg Ala Leu LeuAla Leu Gln 260 265 270 Trp Gly Leu Leu Ser Ala Ala Pro His Asp 275 28075 849 DNA Homo sapiens CDS (1)...(849) 75 atg aag gtc aag gtc atc cccgtg ctc gag gac aac tac atg tac ctg 48 Met Lys Val Lys Val Ile Pro ValLeu Glu Asp Asn Tyr Met Tyr Leu 1 5 10 15 gtc atc gag gag ctc acg cgcgag gcg gtg gcc gtg gac gtg gct gtg 96 Val Ile Glu Glu Leu Thr Arg GluAla Val Ala Val Asp Val Ala Val 20 25 30 ccc aag agg ctg ctg gag atc gtgggc cgg gag ggg gtg tct ctg acc 144 Pro Lys Arg Leu Leu Glu Ile Val GlyArg Glu Gly Val Ser Leu Thr 35 40 45 gct gtg ctg acc acc cac cat cac tgggac cac gcg cgg gga aac ccg 192 Ala Val Leu Thr Thr His His His Trp AspHis Ala Arg Gly Asn Pro 50 55 60 gag ctg gcg cgg ctt cgt ccc ggg ctg gcggtg ctg ggc gcg gac gag 240 Glu Leu Ala Arg Leu Arg Pro Gly Leu Ala ValLeu Gly Ala Asp Glu 65 70 75 80 cgc atc ttc tcg ctg acg cgc agg ctg gcgcac ggc gag gag ctg cgg 288 Arg Ile Phe Ser Leu Thr Arg Arg Leu Ala HisGly Glu Glu Leu Arg 85 90 95 ttc ggg gcc atc cac gtg cgt tgc ctc ctg acgccc ggc cac acc gcc 336 Phe Gly Ala Ile His Val Arg Cys Leu Leu Thr ProGly His Thr Ala 100 105 110 ggc cac atg agc tac ttc ctg tgg gag gac gattgc ccg gac cca ccc 384 Gly His Met Ser Tyr Phe Leu Trp Glu Asp Asp CysPro Asp Pro Pro 115 120 125 gcc ctg ttc tcg ggc gac gcg ctg tcg gtg gccggc tgc ggc tcg tgc 432 Ala Leu Phe Ser Gly Asp Ala Leu Ser Val Ala GlyCys Gly Ser Cys 130 135 140 ctg gag ggc agc gcc cag cag atg tac cag agcctg gcc gag ctg ggt 480 Leu Glu Gly Ser Ala Gln Gln Met Tyr Gln Ser LeuAla Glu Leu Gly 145 150 155 160 acc ctg ccc ccc gag acg aag gtg ttc tgcggc cac gag cac acg ctt 528 Thr Leu Pro Pro Glu Thr Lys Val Phe Cys GlyHis Glu His Thr Leu 165 170 175 agc aac ctg gag ttt gcc cag aaa gtg gagccc tgc aac gac cac gtg 576 Ser Asn Leu Glu Phe Ala Gln Lys Val Glu ProCys Asn Asp His Val 180 185 190 aga gcc aag ctg tcc tgg gct aag aag agggat gag gat gac gtg ccc 624 Arg Ala Lys Leu Ser Trp Ala Lys Lys Arg AspGlu Asp Asp Val Pro 195 200 205 act gtg ccg tcg act ctg ggc gag gag cgcctc tac aac ccc ttc ctg 672 Thr Val Pro Ser Thr Leu Gly Glu Glu Arg LeuTyr Asn Pro Phe Leu 210 215 220 cgg gtg gca gag gag ccg gtg cgc aag ttcacg ggc aag gcg gtc ccc 720 Arg Val Ala Glu Glu Pro Val Arg Lys Phe ThrGly Lys Ala Val Pro 225 230 235 240 gcc gac gtc ctg gag gcg cta tgc aaggag cgg gcg cgc ttc gaa cag 768 Ala Asp Val Leu Glu Ala Leu Cys Lys GluArg Ala Arg Phe Glu Gln 245 250 255 gcg ggc gag ccg cgg cag cca cag gcgcgg gcc ctc ctt gcg ctg cag 816 Ala Gly Glu Pro Arg Gln Pro Gln Ala ArgAla Leu Leu Ala Leu Gln 260 265 270 tgg ggg ctc ctg agt gca gcc cca cacgac tga 849 Trp Gly Leu Leu Ser Ala Ala Pro His Asp * 275 280 76 2853DNA Homo sapiens CDS (1)...(2853) 76 atg ctt ctg ctg ggc atc cta acc ctggct ttc gcc ggg cga acc gct 48 Met Leu Leu Leu Gly Ile Leu Thr Leu AlaPhe Ala Gly Arg Thr Ala 1 5 10 15 gga ggc tct gag cca gag cgg gag gtagtc gtt ccc atc cga ctg gac 96 Gly Gly Ser Glu Pro Glu Arg Glu Val ValVal Pro Ile Arg Leu Asp 20 25 30 ccg gac att aac ggc cgc cgc tac tac tggcgg ggt ccc gag gac tcc 144 Pro Asp Ile Asn Gly Arg Arg Tyr Tyr Trp ArgGly Pro Glu Asp Ser 35 40 45 ggg gat cag gga ctc att ttt cag atc aca gcattt cag gag gac ttt 192 Gly Asp Gln Gly Leu Ile Phe Gln Ile Thr Ala PheGln Glu Asp Phe 50 55 60 tac cta cac ctg acg ccg gat gct cag ttc ttg gctccc gcc ttc tcc 240 Tyr Leu His Leu Thr Pro Asp Ala Gln Phe Leu Ala ProAla Phe Ser 65 70 75 80 act gag cat ctg ggc gtc ccc ctc cag ggg ctc accggg ggc tct tca 288 Thr Glu His Leu Gly Val Pro Leu Gln Gly Leu Thr GlyGly Ser Ser 85 90 95 gac ctg cga cgc tgc ttc tat tct ggg gac gtg aac gccgag ccg gac 336 Asp Leu Arg Arg Cys Phe Tyr Ser Gly Asp Val Asn Ala GluPro Asp 100 105 110 tcg ttc gct gct gtg agc ctg tgc ggg ggg ctc cgc ggagcc ttt ggc 384 Ser Phe Ala Ala Val Ser Leu Cys Gly Gly Leu Arg Gly AlaPhe Gly 115 120 125 tac cga ggc gcc gag tat gtc att agc ccg ctg ccc aatgct agc gcg 432 Tyr Arg Gly Ala Glu Tyr Val Ile Ser Pro Leu Pro Asn AlaSer Ala 130 135 140 ccg gcg gcg cag cgc aac agc cag ggc gca cac ctt ctccag cgc cgg 480 Pro Ala Ala Gln Arg Asn Ser Gln Gly Ala His Leu Leu GlnArg Arg 145 150 155 160 ggt gtt ccg ggc ggg cct tcc gga gac ccc acc tctcgc tgc ggg gtg 528 Gly Val Pro Gly Gly Pro Ser Gly Asp Pro Thr Ser ArgCys Gly Val 165 170 175 gcc tcg ggc tgg aac ccc gcc atc cta cgg gcc ctggac cct tac aag 576 Ala Ser Gly Trp Asn Pro Ala Ile Leu Arg Ala Leu AspPro Tyr Lys 180 185 190 ccg cgg cgg gcg ggc ttc ggg gag agt cgt agc cggcgc agg tct ggg 624 Pro Arg Arg Ala Gly Phe Gly Glu Ser Arg Ser Arg ArgArg Ser Gly 195 200 205 cgc gcc aag cgt ttc gtg tct atc ccg cgg tac gtggag acg ctg gtg 672 Arg Ala Lys Arg Phe Val Ser Ile Pro Arg Tyr Val GluThr Leu Val 210 215 220 gtc gcg gac gag tca atg gtc aag ttc cac ggc gcggac ctg gaa cat 720 Val Ala Asp Glu Ser Met Val Lys Phe His Gly Ala AspLeu Glu His 225 230 235 240 tat ctg ctg acg ctg ctg gca acg gcg gcg cgactc tac cgc cat ccc 768 Tyr Leu Leu Thr Leu Leu Ala Thr Ala Ala Arg LeuTyr Arg His Pro 245 250 255 agc atc ctc aac ccc atc aac atc gtt gtg gtcaag gtg ctg ctt ctt 816 Ser Ile Leu Asn Pro Ile Asn Ile Val Val Val LysVal Leu Leu Leu 260 265 270 aga gat cgt gac tcc ggg ccc aag gtc acc ggcaat gcg gcc ctg acg 864 Arg Asp Arg Asp Ser Gly Pro Lys Val Thr Gly AsnAla Ala Leu Thr 275 280 285 ctg cgc aac ttc tgt gcc tgg cag aag aag ctgaac aaa gtg agt gac 912 Leu Arg Asn Phe Cys Ala Trp Gln Lys Lys Leu AsnLys Val Ser Asp 290 295 300 aag cac ccc gag tac tgg gac act gcc atc ctcttc acc agg cag gac 960 Lys His Pro Glu Tyr Trp Asp Thr Ala Ile Leu PheThr Arg Gln Asp 305 310 315 320 ctg tgt gga gcc acc acc tgt gac acc ctgggc atg gct gat gtg ggt 1008 Leu Cys Gly Ala Thr Thr Cys Asp Thr Leu GlyMet Ala Asp Val Gly 325 330 335 acc atg tgt gac ccc aag aga agc tgc tctgtc att gag gac gat ggg 1056 Thr Met Cys Asp Pro Lys Arg Ser Cys Ser ValIle Glu Asp Asp Gly 340 345 350 ctt cca tca gcc ttc acc act gcc cac gagctg ggc cac gtg ttc aac 1104 Leu Pro Ser Ala Phe Thr Thr Ala His Glu LeuGly His Val Phe Asn 355 360 365 atg ccc cat gac aat gtg aaa gtc tgt gaggag gtg ttt ggg aag ctc 1152 Met Pro His Asp Asn Val Lys Val Cys Glu GluVal Phe Gly Lys Leu 370 375 380 cga gcc aac cac atg atg tcc ccg acc ctcatc cag atc gac cgt gcc 1200 Arg Ala Asn His Met Met Ser Pro Thr Leu IleGln Ile Asp Arg Ala 385 390 395 400 aac ccc tgg tca gcc tgc agt gct gccatc atc acc gac ttc ctg gac 1248 Asn Pro Trp Ser Ala Cys Ser Ala Ala IleIle Thr Asp Phe Leu Asp 405 410 415 agc ggg cac ggt gac tgc ctc ctg gaccaa ccc agc aag ccc atc tcc 1296 Ser Gly His Gly Asp Cys Leu Leu Asp GlnPro Ser Lys Pro Ile Ser 420 425 430 ctg ccc gag gat ctg ccg ggc gcc agctac acc ctg agc cag cag tgc 1344 Leu Pro Glu Asp Leu Pro Gly Ala Ser TyrThr Leu Ser Gln Gln Cys 435 440 445 gag ctg gct ttt ggc gtg ggc tcc aagccc tgt cct tac atg cag tac 1392 Glu Leu Ala Phe Gly Val Gly Ser Lys ProCys Pro Tyr Met Gln Tyr 450 455 460 tgc acc aag ctg tgg tgc acc ggg aaggcc aag gga cag atg gtg tgc 1440 Cys Thr Lys Leu Trp Cys Thr Gly Lys AlaLys Gly Gln Met Val Cys 465 470 475 480 cag acc cgc cac ttc ccc tgg gccgat ggc acc agc tgt ggc gag ggc 1488 Gln Thr Arg His Phe Pro Trp Ala AspGly Thr Ser Cys Gly Glu Gly 485 490 495 aag ctc tgc ctc aaa ggg gcc tgcgtg gag aga cac aac ctc aac aag 1536 Lys Leu Cys Leu Lys Gly Ala Cys ValGlu Arg His Asn Leu Asn Lys 500 505 510 cac agg gtg gat ggt tcc tgg gccaaa tgg gat ccc tat ggc ccc tgc 1584 His Arg Val Asp Gly Ser Trp Ala LysTrp Asp Pro Tyr Gly Pro Cys 515 520 525 tcg cgc aca tgt ggt ggg ggc gtgcag ctg gcc agg agg cag tgc acc 1632 Ser Arg Thr Cys Gly Gly Gly Val GlnLeu Ala Arg Arg Gln Cys Thr 530 535 540 aac ccc acc cct gcc aac ggg ggcaag tac tgc gag gga gtg agg gtg 1680 Asn Pro Thr Pro Ala Asn Gly Gly LysTyr Cys Glu Gly Val Arg Val 545 550 555 560 aaa tac cga tcc tgc aat ctggag ccc tgc ccc agc tca gcc tcc gga 1728 Lys Tyr Arg Ser Cys Asn Leu GluPro Cys Pro Ser Ser Ala Ser Gly 565 570 575 aag agc ttc cgg gag gag cagtgt gag gct ttc aac ggc tac aac cac 1776 Lys Ser Phe Arg Glu Glu Gln CysGlu Ala Phe Asn Gly Tyr Asn His 580 585 590 agc acc aac cgg ctc act ctcgcc gtg gca tgg gtg ccc aag tac tcc 1824 Ser Thr Asn Arg Leu Thr Leu AlaVal Ala Trp Val Pro Lys Tyr Ser 595 600 605 ggc gtg tct ccc cgg gac aagtgc aag ctc atc tgc cga gcc aat ggc 1872 Gly Val Ser Pro Arg Asp Lys CysLys Leu Ile Cys Arg Ala Asn Gly 610 615 620 act ggc tac ttc tat gtg ctggca ccc aag gtg gtg gac ggc acg ctg 1920 Thr Gly Tyr Phe Tyr Val Leu AlaPro Lys Val Val Asp Gly Thr Leu 625 630 635 640 tgc tct cct gac tcc acctcc gtc tgt gtc caa ggc aag tgc atc aag 1968 Cys Ser Pro Asp Ser Thr SerVal Cys Val Gln Gly Lys Cys Ile Lys 645 650 655 gct ggc tgt gat ggg aacctg ggc tcc aag aag aga ttc gac aag tgt 2016 Ala Gly Cys Asp Gly Asn LeuGly Ser Lys Lys Arg Phe Asp Lys Cys 660 665 670 ggg gtg tgt ggg gga gacaat aag agc tgc aag aag gtg act gga ctc 2064 Gly Val Cys Gly Gly Asp AsnLys Ser Cys Lys Lys Val Thr Gly Leu 675 680 685 ttc acc aag ccc atg catggc tac aat ttc gtg gtg gcc atc ccc gca 2112 Phe Thr Lys Pro Met His GlyTyr Asn Phe Val Val Ala Ile Pro Ala 690 695 700 ggc gcc tca agc atc gacatc cgc cag cgc ggt tac aaa ggg ctg atc 2160 Gly Ala Ser Ser Ile Asp IleArg Gln Arg Gly Tyr Lys Gly Leu Ile 705 710 715 720 ggg gat gac aac tacctg gct ctg aag aac agc caa ggc aag tac ctg 2208 Gly Asp Asp Asn Tyr LeuAla Leu Lys Asn Ser Gln Gly Lys Tyr Leu 725 730 735 ctc aac ggg cat ttcgtg gtg tcg gcg gtg gag cgg gac ctg gtg gtg 2256 Leu Asn Gly His Phe ValVal Ser Ala Val Glu Arg Asp Leu Val Val 740 745 750 aag ggc agt ctg ctgcgg tac agc ggc acg ggc aca gcg gtg gag agc 2304 Lys Gly Ser Leu Leu ArgTyr Ser Gly Thr Gly Thr Ala Val Glu Ser 755 760 765 ctg cag gct tcc cggccc atc ctg gag ccg ctg acc gtg gag gtc ctc 2352 Leu Gln Ala Ser Arg ProIle Leu Glu Pro Leu Thr Val Glu Val Leu 770 775 780 tcc gtg ggg aag atgaca ccg ccc cgg gtc cgc tac tcc ttc tat ctg 2400 Ser Val Gly Lys Met ThrPro Pro Arg Val Arg Tyr Ser Phe Tyr Leu 785 790 795 800 ccc aaa gag cctcgg gag gac aag tcc tct cat ccc aag gac ccc cgg 2448 Pro Lys Glu Pro ArgGlu Asp Lys Ser Ser His Pro Lys Asp Pro Arg 805 810 815 gga ccc tct gtcttg cac aac agc gtc ctc agc ctc tcc aac cag gtg 2496 Gly Pro Ser Val LeuHis Asn Ser Val Leu Ser Leu Ser Asn Gln Val 820 825 830 gag cag ccg gacgac agg ccc cct gca cgc tgg gtg gct ggc agc tgg 2544 Glu Gln Pro Asp AspArg Pro Pro Ala Arg Trp Val Ala Gly Ser Trp 835 840 845 ggg ccg tgc tccgcg agc tgc ggc agt ggc ctg cag aag cgg gcg gtg 2592 Gly Pro Cys Ser AlaSer Cys Gly Ser Gly Leu Gln Lys Arg Ala Val 850 855 860 gac tgc cgg ggctcc gcc ggg cag cgc acg gtc cct gcc tgt gat gca 2640 Asp Cys Arg Gly SerAla Gly Gln Arg Thr Val Pro Ala Cys Asp Ala 865 870 875 880 gcc cat cggccc gtg gag aca caa gcc tgc ggg gag ccc tgc ccc acc 2688 Ala His Arg ProVal Glu Thr Gln Ala Cys Gly Glu Pro Cys Pro Thr 885 890 895 tgg gag ctcagc gcc tgg tca ccc tgc tcc aag agc tgc ggc cgg gga 2736 Trp Glu Leu SerAla Trp Ser Pro Cys Ser Lys Ser Cys Gly Arg Gly 900 905 910 ttt cag aggcgc tca ctc aag tgt gtg ggc cac gga ggc cgg ctg ctg 2784 Phe Gln Arg ArgSer Leu Lys Cys Val Gly His Gly Gly Arg Leu Leu 915 920 925 gcc cgg gaccag tgc aac ttg cac cgc aag ccc cag gag ctg gac ttc 2832 Ala Arg Asp GlnCys Asn Leu His Arg Lys Pro Gln Glu Leu Asp Phe 930 935 940 tgc gtc ctgagg ccg tgc tga 2853 Cys Val Leu Arg Pro Cys * 945 950 77 950 PRT Homosapiens 77 Met Leu Leu Leu Gly Ile Leu Thr Leu Ala Phe Ala Gly Arg ThrAla 1 5 10 15 Gly Gly Ser Glu Pro Glu Arg Glu Val Val Val Pro Ile ArgLeu Asp 20 25 30 Pro Asp Ile Asn Gly Arg Arg Tyr Tyr Trp Arg Gly Pro GluAsp Ser 35 40 45 Gly Asp Gln Gly Leu Ile Phe Gln Ile Thr Ala Phe Gln GluAsp Phe 50 55 60 Tyr Leu His Leu Thr Pro Asp Ala Gln Phe Leu Ala Pro AlaPhe Ser 65 70 75 80 Thr Glu His Leu Gly Val Pro Leu Gln Gly Leu Thr GlyGly Ser Ser 85 90 95 Asp Leu Arg Arg Cys Phe Tyr Ser Gly Asp Val Asn AlaGlu Pro Asp 100 105 110 Ser Phe Ala Ala Val Ser Leu Cys Gly Gly Leu ArgGly Ala Phe Gly 115 120 125 Tyr Arg Gly Ala Glu Tyr Val Ile Ser Pro LeuPro Asn Ala Ser Ala 130 135 140 Pro Ala Ala Gln Arg Asn Ser Gln Gly AlaHis Leu Leu Gln Arg Arg 145 150 155 160 Gly Val Pro Gly Gly Pro Ser GlyAsp Pro Thr Ser Arg Cys Gly Val 165 170 175 Ala Ser Gly Trp Asn Pro AlaIle Leu Arg Ala Leu Asp Pro Tyr Lys 180 185 190 Pro Arg Arg Ala Gly PheGly Glu Ser Arg Ser Arg Arg Arg Ser Gly 195 200 205 Arg Ala Lys Arg PheVal Ser Ile Pro Arg Tyr Val Glu Thr Leu Val 210 215 220 Val Ala Asp GluSer Met Val Lys Phe His Gly Ala Asp Leu Glu His 225 230 235 240 Tyr LeuLeu Thr Leu Leu Ala Thr Ala Ala Arg Leu Tyr Arg His Pro 245 250 255 SerIle Leu Asn Pro Ile Asn Ile Val Val Val Lys Val Leu Leu Leu 260 265 270Arg Asp Arg Asp Ser Gly Pro Lys Val Thr Gly Asn Ala Ala Leu Thr 275 280285 Leu Arg Asn Phe Cys Ala Trp Gln Lys Lys Leu Asn Lys Val Ser Asp 290295 300 Lys His Pro Glu Tyr Trp Asp Thr Ala Ile Leu Phe Thr Arg Gln Asp305 310 315 320 Leu Cys Gly Ala Thr Thr Cys Asp Thr Leu Gly Met Ala AspVal Gly 325 330 335 Thr Met Cys Asp Pro Lys Arg Ser Cys Ser Val Ile GluAsp Asp Gly 340 345 350 Leu Pro Ser Ala Phe Thr Thr Ala His Glu Leu GlyHis Val Phe Asn 355 360 365 Met Pro His Asp Asn Val Lys Val Cys Glu GluVal Phe Gly Lys Leu 370 375 380 Arg Ala Asn His Met Met Ser Pro Thr LeuIle Gln Ile Asp Arg Ala 385 390 395 400 Asn Pro Trp Ser Ala Cys Ser AlaAla Ile Ile Thr Asp Phe Leu Asp 405 410 415 Ser Gly His Gly Asp Cys LeuLeu Asp Gln Pro Ser Lys Pro Ile Ser 420 425 430 Leu Pro Glu Asp Leu ProGly Ala Ser Tyr Thr Leu Ser Gln Gln Cys 435 440 445 Glu Leu Ala Phe GlyVal Gly Ser Lys Pro Cys Pro Tyr Met Gln Tyr 450 455 460 Cys Thr Lys LeuTrp Cys Thr Gly Lys Ala Lys Gly Gln Met Val Cys 465 470 475 480 Gln ThrArg His Phe Pro Trp Ala Asp Gly Thr Ser Cys Gly Glu Gly 485 490 495 LysLeu Cys Leu Lys Gly Ala Cys Val Glu Arg His Asn Leu Asn Lys 500 505 510His Arg Val Asp Gly Ser Trp Ala Lys Trp Asp Pro Tyr Gly Pro Cys 515 520525 Ser Arg Thr Cys Gly Gly Gly Val Gln Leu Ala Arg Arg Gln Cys Thr 530535 540 Asn Pro Thr Pro Ala Asn Gly Gly Lys Tyr Cys Glu Gly Val Arg Val545 550 555 560 Lys Tyr Arg Ser Cys Asn Leu Glu Pro Cys Pro Ser Ser AlaSer Gly 565 570 575 Lys Ser Phe Arg Glu Glu Gln Cys Glu Ala Phe Asn GlyTyr Asn His 580 585 590 Ser Thr Asn Arg Leu Thr Leu Ala Val Ala Trp ValPro Lys Tyr Ser 595 600 605 Gly Val Ser Pro Arg Asp Lys Cys Lys Leu IleCys Arg Ala Asn Gly 610 615 620 Thr Gly Tyr Phe Tyr Val Leu Ala Pro LysVal Val Asp Gly Thr Leu 625 630 635 640 Cys Ser Pro Asp Ser Thr Ser ValCys Val Gln Gly Lys Cys Ile Lys 645 650 655 Ala Gly Cys Asp Gly Asn LeuGly Ser Lys Lys Arg Phe Asp Lys Cys 660 665 670 Gly Val Cys Gly Gly AspAsn Lys Ser Cys Lys Lys Val Thr Gly Leu 675 680 685 Phe Thr Lys Pro MetHis Gly Tyr Asn Phe Val Val Ala Ile Pro Ala 690 695 700 Gly Ala Ser SerIle Asp Ile Arg Gln Arg Gly Tyr Lys Gly Leu Ile 705 710 715 720 Gly AspAsp Asn Tyr Leu Ala Leu Lys Asn Ser Gln Gly Lys Tyr Leu 725 730 735 LeuAsn Gly His Phe Val Val Ser Ala Val Glu Arg Asp Leu Val Val 740 745 750Lys Gly Ser Leu Leu Arg Tyr Ser Gly Thr Gly Thr Ala Val Glu Ser 755 760765 Leu Gln Ala Ser Arg Pro Ile Leu Glu Pro Leu Thr Val Glu Val Leu 770775 780 Ser Val Gly Lys Met Thr Pro Pro Arg Val Arg Tyr Ser Phe Tyr Leu785 790 795 800 Pro Lys Glu Pro Arg Glu Asp Lys Ser Ser His Pro Lys AspPro Arg 805 810 815 Gly Pro Ser Val Leu His Asn Ser Val Leu Ser Leu SerAsn Gln Val 820 825 830 Glu Gln Pro Asp Asp Arg Pro Pro Ala Arg Trp ValAla Gly Ser Trp 835 840 845 Gly Pro Cys Ser Ala Ser Cys Gly Ser Gly LeuGln Lys Arg Ala Val 850 855 860 Asp Cys Arg Gly Ser Ala Gly Gln Arg ThrVal Pro Ala Cys Asp Ala 865 870 875 880 Ala His Arg Pro Val Glu Thr GlnAla Cys Gly Glu Pro Cys Pro Thr 885 890 895 Trp Glu Leu Ser Ala Trp SerPro Cys Ser Lys Ser Cys Gly Arg Gly 900 905 910 Phe Gln Arg Arg Ser LeuLys Cys Val Gly His Gly Gly Arg Leu Leu 915 920 925 Ala Arg Asp Gln CysAsn Leu His Arg Lys Pro Gln Glu Leu Asp Phe 930 935 940 Cys Val Leu ArgPro Cys 945 950 78 2853 DNA Homo sapiens CDS (1)...(2853) 78 atg ctt ctgctg ggc atc cta acc ctg gct ttc gcc ggg cga acc gct 48 Met Leu Leu LeuGly Ile Leu Thr Leu Ala Phe Ala Gly Arg Thr Ala 1 5 10 15 gga ggc tctgag cca gag cgg gag gta gtc gtt ccc atc cga ctg gac 96 Gly Gly Ser GluPro Glu Arg Glu Val Val Val Pro Ile Arg Leu Asp 20 25 30 ccg gac att aacggc cgc cgc tac tac tgg cgg ggt ccc gag gac tcc 144 Pro Asp Ile Asn GlyArg Arg Tyr Tyr Trp Arg Gly Pro Glu Asp Ser 35 40 45 ggg gat cag gga ctcatt ttt cag atc aca gca ttt cag gag gac ttt 192 Gly Asp Gln Gly Leu IlePhe Gln Ile Thr Ala Phe Gln Glu Asp Phe 50 55 60 tac cta cac ctg acg ccggat gct cag ttc ttg gct ccc gcc ttc tcc 240 Tyr Leu His Leu Thr Pro AspAla Gln Phe Leu Ala Pro Ala Phe Ser 65 70 75 80 act gag cat ctg ggc gtcccc ctc cag ggg ctc acc ggg ggc tct tca 288 Thr Glu His Leu Gly Val ProLeu Gln Gly Leu Thr Gly Gly Ser Ser 85 90 95 gac ctg cga cgc tgc ttc tattct ggg gac gtg aac gcc gag ccg gac 336 Asp Leu Arg Arg Cys Phe Tyr SerGly Asp Val Asn Ala Glu Pro Asp 100 105 110 tcg ttc gct gct gtg agc ctgtgc ggg ggg ctc cgc gga gcc ttt ggc 384 Ser Phe Ala Ala Val Ser Leu CysGly Gly Leu Arg Gly Ala Phe Gly 115 120 125 tac cga ggc gcc gag tat gtcatt agc ccg ctg ccc aat gct agc gcg 432 Tyr Arg Gly Ala Glu Tyr Val IleSer Pro Leu Pro Asn Ala Ser Ala 130 135 140 ccg gcg gcg cag cgc aac agccag ggc gca cac ctt ctc cag cgc cgg 480 Pro Ala Ala Gln Arg Asn Ser GlnGly Ala His Leu Leu Gln Arg Arg 145 150 155 160 ggt gtt ccg ggc ggg ccttcc gga gac ccc acc tct cgc tgc ggg gtg 528 Gly Val Pro Gly Gly Pro SerGly Asp Pro Thr Ser Arg Cys Gly Val 165 170 175 gcc tcg ggc tgg aac cccgcc atc cta cgg gcc ctg gac cct tac aag 576 Ala Ser Gly Trp Asn Pro AlaIle Leu Arg Ala Leu Asp Pro Tyr Lys 180 185 190 ccg cgg cgg gcg ggc ttcggg gag agt cgt agc cgg cgc agg tct ggg 624 Pro Arg Arg Ala Gly Phe GlyGlu Ser Arg Ser Arg Arg Arg Ser Gly 195 200 205 cgc gcc aag cgt ttc gtgtct atc ccg cgg tac gtg gag acg ctg gtg 672 Arg Ala Lys Arg Phe Val SerIle Pro Arg Tyr Val Glu Thr Leu Val 210 215 220 gtc gcg gac gag tca atggtc aag ttc cac ggc gcg gac ctg gaa cat 720 Val Ala Asp Glu Ser Met ValLys Phe His Gly Ala Asp Leu Glu His 225 230 235 240 tat ctg ctg acg ctgctg gca acg gcg gcg cga ctc tac cgc cat ccc 768 Tyr Leu Leu Thr Leu LeuAla Thr Ala Ala Arg Leu Tyr Arg His Pro 245 250 255 agc atc ctc aac cccatc aac atc gtt gtg gtc aag gtg ctg ctt ctt 816 Ser Ile Leu Asn Pro IleAsn Ile Val Val Val Lys Val Leu Leu Leu 260 265 270 aga gat cgt gac tccggg ccc aag gtc acc ggc aat gcg gcc ctg acg 864 Arg Asp Arg Asp Ser GlyPro Lys Val Thr Gly Asn Ala Ala Leu Thr 275 280 285 ctg cgc aac ttc tgtgcc tgg cag aag aag ctg aac aaa gtg agt gac 912 Leu Arg Asn Phe Cys AlaTrp Gln Lys Lys Leu Asn Lys Val Ser Asp 290 295 300 aag cac ccc gag tactgg gac act gcc atc ctc ttc acc agg cag gac 960 Lys His Pro Glu Tyr TrpAsp Thr Ala Ile Leu Phe Thr Arg Gln Asp 305 310 315 320 ctg tgt gga gccacc acc tgt gac acc ctg ggc atg gct gat gtg ggt 1008 Leu Cys Gly Ala ThrThr Cys Asp Thr Leu Gly Met Ala Asp Val Gly 325 330 335 acc atg tgt gacccc aag aga agc tgc tct gtc att gag gac gat ggg 1056 Thr Met Cys Asp ProLys Arg Ser Cys Ser Val Ile Glu Asp Asp Gly 340 345 350 ctt cca tca gccttc acc act gcc cac gag ctg ggc cac gtg ttc aac 1104 Leu Pro Ser Ala PheThr Thr Ala His Glu Leu Gly His Val Phe Asn 355 360 365 atg ccc cat gacaat gtg aaa gtc tgt gag gag gtg ttt ggg aag ctc 1152 Met Pro His Asp AsnVal Lys Val Cys Glu Glu Val Phe Gly Lys Leu 370 375 380 cga gcc aac cacatg atg tcc ccg acc ctc atc cag atc gac cgt gcc 1200 Arg Ala Asn His MetMet Ser Pro Thr Leu Ile Gln Ile Asp Arg Ala 385 390 395 400 aac ccc tggtca gcc tgc agt gct gcc atc atc acc gac ttc ctg gac 1248 Asn Pro Trp SerAla Cys Ser Ala Ala Ile Ile Thr Asp Phe Leu Asp 405 410 415 agc ggg cacggt gac tgc ctc ctg gac caa ccc agc aag ccc atc tcc 1296 Ser Gly His GlyAsp Cys Leu Leu Asp Gln Pro Ser Lys Pro Ile Ser 420 425 430 ctg ccc gaggat ctg ccg ggc gcc agc tac acc ctg agc cag cag tgc 1344 Leu Pro Glu AspLeu Pro Gly Ala Ser Tyr Thr Leu Ser Gln Gln Cys 435 440 445 gag ctg gctttt ggc gtg ggc tcc aag ccc tgt cct tac atg cag tac 1392 Glu Leu Ala PheGly Val Gly Ser Lys Pro Cys Pro Tyr Met Gln Tyr 450 455 460 tgc acc aagctg tgg tgc acc ggg aag gcc aag gga cag atg gtg tgc 1440 Cys Thr Lys LeuTrp Cys Thr Gly Lys Ala Lys Gly Gln Met Val Cys 465 470 475 480 cag acccgc cac ttc ccc tgg gcc gat ggc acc agc tgt ggc gag ggc 1488 Gln Thr ArgHis Phe Pro Trp Ala Asp Gly Thr Ser Cys Gly Glu Gly 485 490 495 aag ctctgc ctc aaa ggg gcc tgc gtg gag aga cac aac ctc aac aag 1536 Lys Leu CysLeu Lys Gly Ala Cys Val Glu Arg His Asn Leu Asn Lys 500 505 510 cac agggtg gat ggt tcc tgg gcc aaa tgg gat ccc tat ggc ccc tgc 1584 His Arg ValAsp Gly Ser Trp Ala Lys Trp Asp Pro Tyr Gly Pro Cys 515 520 525 tcg cgcaca tgt ggt ggg ggc gtg cag ctg gcc agg agg cag tgc acc 1632 Ser Arg ThrCys Gly Gly Gly Val Gln Leu Ala Arg Arg Gln Cys Thr 530 535 540 aac cccacc cct gcc aac ggg ggc aag tac tgc gag gga gtg agg gtg 1680 Asn Pro ThrPro Ala Asn Gly Gly Lys Tyr Cys Glu Gly Val Arg Val 545 550 555 560 aaatac cga tcc tgc aat ctg gag ccc tgc ccc agc tca gcc tcc gga 1728 Lys TyrArg Ser Cys Asn Leu Glu Pro Cys Pro Ser Ser Ala Ser Gly 565 570 575 aagagc ttc cgg gag gag cag tgt gag gct ttc aac ggc tac aac cac 1776 Lys SerPhe Arg Glu Glu Gln Cys Glu Ala Phe Asn Gly Tyr Asn His 580 585 590 agcacc aac cgg ctc act ctc gcc gtg gca tgg gtg ccc aag tac tcc 1824 Ser ThrAsn Arg Leu Thr Leu Ala Val Ala Trp Val Pro Lys Tyr Ser 595 600 605 ggcgtg tct ccc cgg gac aag tgc aag ctc atc tgc cga gcc aat ggc 1872 Gly ValSer Pro Arg Asp Lys Cys Lys Leu Ile Cys Arg Ala Asn Gly 610 615 620 actggc tac ttc tat gtg ctg gca ccc aag gtg gtg gac ggc acg ctg 1920 Thr GlyTyr Phe Tyr Val Leu Ala Pro Lys Val Val Asp Gly Thr Leu 625 630 635 640tgc tct cct gac tcc acc tcc gtc tgt gtc caa ggc aag tgc atc aag 1968 CysSer Pro Asp Ser Thr Ser Val Cys Val Gln Gly Lys Cys Ile Lys 645 650 655gct ggc tgt gat ggg aac ctg ggc tcc aag aag aga ttc gac aag tgt 2016 AlaGly Cys Asp Gly Asn Leu Gly Ser Lys Lys Arg Phe Asp Lys Cys 660 665 670ggg gtg tgt ggg gga gac aat aag agc tgc aag aag gtg act gga ctc 2064 GlyVal Cys Gly Gly Asp Asn Lys Ser Cys Lys Lys Val Thr Gly Leu 675 680 685ttc acc aag ccc atg cat ggc tac aat ttc gtg gtg gcc atc ccc gca 2112 PheThr Lys Pro Met His Gly Tyr Asn Phe Val Val Ala Ile Pro Ala 690 695 700ggc gcc tca agc atc gac atc cgc cag cgc ggt tac aaa ggg ctg atc 2160 GlyAla Ser Ser Ile Asp Ile Arg Gln Arg Gly Tyr Lys Gly Leu Ile 705 710 715720 ggg gat gac aac tac ctg gct ctg aag aac agc caa ggc aag tac ctg 2208Gly Asp Asp Asn Tyr Leu Ala Leu Lys Asn Ser Gln Gly Lys Tyr Leu 725 730735 ctc aac ggg cat ttc gtg gtg tcg gcg gtg gag cgg gac ctg gtg gtg 2256Leu Asn Gly His Phe Val Val Ser Ala Val Glu Arg Asp Leu Val Val 740 745750 aag ggc agt ctg ctg cgg tac agc ggc acg ggc aca gcg gtg gag agc 2304Lys Gly Ser Leu Leu Arg Tyr Ser Gly Thr Gly Thr Ala Val Glu Ser 755 760765 ctg cag gct tcc cgg ccc atc ctg gag ccg ctg acc gtg gag gtc ctc 2352Leu Gln Ala Ser Arg Pro Ile Leu Glu Pro Leu Thr Val Glu Val Leu 770 775780 tcc gtg ggg aag atg aca ccg ccc cgg gtc cgc tac tcc ttc tat ctg 2400Ser Val Gly Lys Met Thr Pro Pro Arg Val Arg Tyr Ser Phe Tyr Leu 785 790795 800 ccc aaa gag cct cgg gag gac aag tcc tct cat ccc aag gac ccc cgg2448 Pro Lys Glu Pro Arg Glu Asp Lys Ser Ser His Pro Lys Asp Pro Arg 805810 815 gga ccc tct gtc ttg cac aac agc gtc ctc agc ctc tcc aac cag gtg2496 Gly Pro Ser Val Leu His Asn Ser Val Leu Ser Leu Ser Asn Gln Val 820825 830 gag cag ccg gac gac agg ccc cct gca cgc tgg gtg gct ggc agc tgg2544 Glu Gln Pro Asp Asp Arg Pro Pro Ala Arg Trp Val Ala Gly Ser Trp 835840 845 ggg ccg tgc tcc gcg agc tgc ggc agt ggc ctg cag aag cgg gcg gtg2592 Gly Pro Cys Ser Ala Ser Cys Gly Ser Gly Leu Gln Lys Arg Ala Val 850855 860 gac tgc cgg ggc tcc gcc ggg cag cgc acg gtc cct gcc tgt gat gca2640 Asp Cys Arg Gly Ser Ala Gly Gln Arg Thr Val Pro Ala Cys Asp Ala 865870 875 880 gcc cat cgg ccc gtg gag aca caa gcc tgc ggg gag ccc tgc cccacc 2688 Ala His Arg Pro Val Glu Thr Gln Ala Cys Gly Glu Pro Cys Pro Thr885 890 895 tgg gag ctc agc gcc tgg tca ccc tgc tcc aag agc tgc ggc cgggga 2736 Trp Glu Leu Ser Ala Trp Ser Pro Cys Ser Lys Ser Cys Gly Arg Gly900 905 910 ttt cag agg cgc tca ctc aag tgt gtg ggc cac gga ggc cgg ctgctg 2784 Phe Gln Arg Arg Ser Leu Lys Cys Val Gly His Gly Gly Arg Leu Leu915 920 925 gcc cgg gac cag tgc aac ttg cac cgc aag ccc cag gag ctg gacttc 2832 Ala Arg Asp Gln Cys Asn Leu His Arg Lys Pro Gln Glu Leu Asp Phe930 935 940 tgc gtc ctg agg ccg tgc tga 2853 Cys Val Leu Arg Pro Cys *945 950 79 119 PRT Artificial Sequence Consensus amino acid sequence 79His Leu Glu Lys Asn Arg Ser Leu Leu Ala Pro Asp Phe Thr Val Thr 1 5 1015 Thr Tyr Asp Glu Asp Gly Thr Leu Val Thr Glu Glu Pro Leu Ile Gln 20 2530 Asp Asp His Cys Tyr Tyr Gln Gly Tyr Val Glu Gly Tyr Pro Asn Ser 35 4045 Ala Val Ser Leu Ser Thr Cys Ser Gly Gly Leu Arg Gly Ile Leu Gln 50 5560 Leu Glu Asn Leu Ser Tyr Gly Ile Glu Pro Leu Glu Ser Ser Asp Gly 65 7075 80 Phe Glu His Ile Ile Tyr Gln Ile Glu Asn Asp Lys Thr Glu Pro Ser 8590 95 Pro Cys Gly Glu Cys Gly Ser Leu Ser Thr Ser Thr Asp Ser Ser Tyr100 105 110 Gly Ile Arg Ser Ala Ser Pro 115 80 203 PRT ArtificialSequence Consensus amino acid sequence 80 Arg Tyr Ile Glu Leu Val IleVal Val Asp His Gly Met Tyr Thr Lys 1 5 10 15 Tyr Gly Ser Asp Leu AsnLys Ile Arg Gln Arg Val His Gln Ile Val 20 25 30 Asn Leu Val Asn Glu IleTyr Arg Pro Gln Leu Asn Ile Arg Val Val 35 40 45 Leu Val Gly Leu Glu IleTrp Ser Asp Gly Asp Lys Ile Asn Val Gln 50 55 60 Ser Asp Ala Asn Asp ThrLeu His Ser Phe Gly Glu Trp Arg Glu Thr 65 70 75 80 Asp Leu Leu Lys ArgLys Ser His Asp Asn Ala Gln Leu Leu Thr Gly 85 90 95 Ile Asp Phe Asp GlyAsn Thr Ile Gly Ala Ala Tyr Val Gly Gly Met 100 105 110 Cys Ser Pro LysArg Ser Val Gly Val Val Gln Asp His Ser Pro Ile 115 120 125 Val Leu LeuVal Ala Val Thr Met Ala His Glu Leu Gly His Asn Leu 130 135 140 Gly MetThr His Asp Asp Lys Asn Lys Asp Gly Cys Thr Cys Pro Gly 145 150 155 160Gly Gly Ser Cys Ile Met Asn Pro Val Ala Ser Ser Ser Pro Ser Lys 165 170175 Lys Lys Phe Ser Asn Cys Ser Lys Asp Asp Tyr Gln Lys Phe Leu Thr 180185 190 Lys Gln Lys Pro Gln Cys Leu Leu Asn Lys Pro 195 200 81 54 PRTArtificial Sequence Consensus amino acid sequence 81 Ser Pro Trp Ser GluTrp Ser Pro Cys Ser Val Thr Cys Gly Lys Gly 1 5 10 15 Ile Arg Thr ArgGln Arg Thr Cys Asn Ser Pro Ala Pro Gln Lys Lys 20 25 30 Gly Gly Lys ProCys Thr Gly Asp Ala Gln Glu Glu Thr Glu Ala Cys 35 40 45 Asp Met Met AspLys Cys 50 82 968 PRT Mus musculus 82 Met Gln Pro Lys Val Pro Leu GlySer Arg Lys Gln Lys Pro Cys Ser 1 5 10 15 Asp Met Gly Asp Val Gln ArgAla Ala Arg Ser Arg Gly Ser Leu Ser 20 25 30 Ala His Met Leu Leu Leu LeuLeu Ala Ser Ile Thr Met Leu Leu Cys 35 40 45 Ala Arg Gly Ala His Gly ArgPro Thr Glu Glu Asp Glu Glu Leu Val 50 55 60 Leu Pro Ser Leu Glu Arg AlaPro Gly His Asp Ser Thr Thr Thr Arg 65 70 75 80 Leu Arg Leu Asp Ala PheGly Gln Gln Leu His Leu Lys Leu Gln Pro 85 90 95 Asp Ser Gly Phe Leu AlaPro Gly Phe Thr Leu Gln Thr Val Gly Arg 100 105 110 Ser Pro Gly Ser GluAla Gln His Leu Asp Pro Thr Gly Asp Leu Ala 115 120 125 His Cys Phe TyrSer Gly Thr Val Asn Gly Asp Pro Gly Ser Ala Ala 130 135 140 Ala Leu SerLeu Cys Glu Gly Val Arg Gly Ala Phe Tyr Leu Gln Gly 145 150 155 160 GluGlu Phe Phe Ile Gln Pro Ala Pro Gly Val Ala Thr Glu Arg Leu 165 170 175Ala Pro Ala Val Pro Glu Glu Glu Ser Ser Ala Arg Pro Gln Phe His 180 185190 Ile Leu Arg Arg Arg Arg Arg Gly Ser Gly Gly Ala Lys Cys Gly Val 195200 205 Met Asp Asp Glu Thr Leu Pro Thr Ser Asp Ser Arg Pro Glu Ser Gln210 215 220 Asn Thr Arg Asn Gln Trp Pro Val Arg Asp Pro Thr Pro Gln AspAla 225 230 235 240 Gly Lys Pro Ser Gly Pro Gly Ser Ile Arg Lys Lys ArgPhe Val Ser 245 250 255 Ser Pro Arg Tyr Val Glu Thr Met Leu Val Ala AspGln Ser Met Ala 260 265 270 Asp Phe His Gly Ser Gly Leu Lys His Tyr LeuLeu Thr Leu Phe Ser 275 280 285 Val Ala Ala Arg Phe Tyr Lys His Pro SerIle Arg Asn Ser Ile Ser 290 295 300 Leu Val Val Val Lys Ile Leu Val IleTyr Glu Glu Gln Lys Gly Pro 305 310 315 320 Glu Val Thr Ser Asn Ala AlaLeu Thr Leu Arg Asn Phe Cys Asn Trp 325 330 335 Gln Lys Gln His Asn SerPro Ser Asp Arg Asp Pro Glu His Tyr Asp 340 345 350 Thr Ala Ile Leu PheThr Arg Gln Asp Leu Cys Gly Ser His Thr Cys 355 360 365 Asp Thr Leu GlyMet Ala Asp Val Gly Thr Val Cys Asp Pro Ser Arg 370 375 380 Ser Cys SerVal Ile Glu Asp Asp Gly Leu Gln Ala Ala Phe Thr Thr 385 390 395 400 AlaHis Glu Leu Gly His Val Phe Asn Met Pro His Asp Asp Ala Lys 405 410 415His Cys Ala Ser Leu Asn Gly Val Thr Gly Asp Ser His Leu Met Ala 420 425430 Ser Met Leu Ser Ser Leu Asp His Ser Gln Pro Trp Ser Pro Cys Ser 435440 445 Ala Tyr Met Val Thr Ser Phe Leu Asp Asn Gly His Gly Glu Cys Leu450 455 460 Met Asp Lys Pro Gln Asn Pro Ile Lys Leu Pro Ser Asp Leu ProGly 465 470 475 480 Thr Leu Tyr Asp Ala Asn Arg Gln Cys Gln Phe Thr PheGly Glu Glu 485 490 495 Ser Lys His Cys Pro Asp Ala Ala Ser Thr Cys ThrThr Leu Trp Cys 500 505 510 Thr Gly Thr Ser Gly Gly Leu Leu Val Cys GlnThr Lys His Phe Pro 515 520 525 Trp Ala Asp Gly Thr Ser Cys Gly Glu GlyLys Trp Cys Val Ser Gly 530 535 540 Lys Cys Val Asn Lys Thr Asp Met LysHis Phe Ala Thr Pro Val His 545 550 555 560 Gly Ser Trp Gly Pro Trp GlyPro Trp Gly Asp Cys Ser Arg Thr Cys 565 570 575 Gly Gly Gly Val Gln TyrThr Met Arg Glu Cys Asp Asn Pro Val Pro 580 585 590 Lys Asn Gly Gly LysTyr Cys Glu Gly Lys Arg Val Arg Tyr Arg Ser 595 600 605 Cys Asn Ile GluAsp Cys Pro Asp Asn Asn Gly Lys Thr Phe Arg Glu 610 615 620 Glu Gln CysGlu Ala His Asn Glu Phe Ser Lys Ala Ser Phe Gly Asn 625 630 635 640 GluPro Thr Val Glu Trp Thr Pro Lys Tyr Ala Gly Val Ser Pro Lys 645 650 655Asp Arg Cys Lys Leu Thr Cys Glu Ala Lys Gly Ile Gly Tyr Phe Phe 660 665670 Val Leu Gln Pro Lys Val Val Asp Gly Thr Pro Cys Ser Pro Asp Ser 675680 685 Thr Ser Val Cys Val Gln Gly Gln Cys Val Lys Ala Gly Cys Asp Arg690 695 700 Ile Ile Asp Ser Lys Lys Lys Phe Asp Lys Cys Gly Val Cys GlyGly 705 710 715 720 Asn Gly Ser Thr Cys Lys Lys Met Ser Gly Ile Val ThrSer Thr Arg 725 730 735 Pro Gly Tyr His Asp Ile Val Thr Ile Pro Ala GlyAla Thr Asn Ile 740 745 750 Glu Val Lys His Arg Asn Gln Arg Gly Ser ArgAsn Asn Gly Ser Phe 755 760 765 Leu Ala Ile Arg Ala Ala Asp Gly Thr TyrIle Leu Asn Gly Asn Phe 770 775 780 Thr Leu Ser Thr Leu Glu Gln Asp LeuThr Tyr Lys Gly Thr Val Leu 785 790 795 800 Arg Tyr Ser Gly Ser Ser AlaAla Leu Glu Arg Ile Arg Ser Phe Ser 805 810 815 Pro Leu Lys Glu Pro LeuThr Ile Gln Val Leu Met Val Gly His Ala 820 825 830 Leu Arg Pro Lys IleLys Phe Thr Tyr Phe Met Lys Lys Lys Thr Glu 835 840 845 Ser Phe Asn AlaIle Pro Thr Phe Ser Glu Trp Val Ile Glu Glu Trp 850 855 860 Gly Glu CysSer Lys Thr Cys Gly Ser Gly Trp Gln Arg Arg Val Val 865 870 875 880 GlnCys Arg Asp Ile Asn Gly His Pro Ala Ser Glu Cys Ala Lys Glu 885 890 895Val Lys Pro Ala Ser Thr Arg Pro Cys Ala Asp Leu Pro Cys Pro His 900 905910 Trp Gln Val Gly Asp Trp Ser Pro Cys Ser Lys Thr Cys Gly Lys Gly 915920 925 Tyr Lys Lys Arg Thr Leu Lys Cys Val Ser His Asp Gly Gly Val Leu930 935 940 Ser Asn Glu Ser Cys Asp Pro Leu Lys Lys Pro Lys His Tyr IleAsp 945 950 955 960 Phe Cys Thr Leu Thr Gln Cys Ser 965 83 10 PRT Homosapiens VARIANT (1)...(1) Xaa position one can be G or S or T or A or Lor I or V or N 83 Xaa Xaa Xaa His Glu Xaa Xaa His Xaa Xaa 1 5 10 84 5PRT Artificial Sequence Consensus amino acid sequence 84 His Glu Xaa XaaHis 1 5 85 22 PRT Artificial Sequence Consensus amino acid sequence 85Leu Xaa Xaa Xaa Xaa Xaa Xaa Leu Xaa Xaa Xaa Xaa Xaa Xaa Leu Xaa 1 5 1015 Xaa Xaa Xaa Xaa Xaa Leu 20 86 3445 DNA Homo sapiens CDS (83)...(3328)86 cggccgcgga aagaatgcgc gccgcccgtg cgctccgcct gccgcgtctg gccacccgca 60gccgccgcgt ccgcacctga cc atg gag tgc gcc ctc ctg ctc gcg tgt gcc 112 MetGlu Cys Ala Leu Leu Leu Ala Cys Ala 1 5 10 ttc ccg gct gcg ggt tcg ggcccg ccg agg ggc ctg gcg gga ctg ggg 160 Phe Pro Ala Ala Gly Ser Gly ProPro Arg Gly Leu Ala Gly Leu Gly 15 20 25 cgc gtg gcc aag gcg ctc cag ctgtgc tgc ctc tgc tgt gcg tcg gtc 208 Arg Val Ala Lys Ala Leu Gln Leu CysCys Leu Cys Cys Ala Ser Val 30 35 40 gcc gcg gcc tta gcc agt gac agc agcagc ggc gcc agc gga tta aat 256 Ala Ala Ala Leu Ala Ser Asp Ser Ser SerGly Ala Ser Gly Leu Asn 45 50 55 gat gat tac gtc ttt gtc acg cca gta gaagta gac tca gcc ggg tca 304 Asp Asp Tyr Val Phe Val Thr Pro Val Glu ValAsp Ser Ala Gly Ser 60 65 70 tat att tca cac gac att ttg cac aac ggc aggaaa aag cga tcg gcg 352 Tyr Ile Ser His Asp Ile Leu His Asn Gly Arg LysLys Arg Ser Ala 75 80 85 90 cag aat gcc aga agc tcc ctg cac tac cga ttttca gca ttt gga cag 400 Gln Asn Ala Arg Ser Ser Leu His Tyr Arg Phe SerAla Phe Gly Gln 95 100 105 gaa ctg cac tta gaa ctt aag ccc tcg gcg attttg agc agt cac ttt 448 Glu Leu His Leu Glu Leu Lys Pro Ser Ala Ile LeuSer Ser His Phe 110 115 120 att gtc cag gta ctt gga aaa gat ggt gct tcagag act cag aaa ccc 496 Ile Val Gln Val Leu Gly Lys Asp Gly Ala Ser GluThr Gln Lys Pro 125 130 135 gag gtg cag caa tgc ttc tat cag gga ttt atcaga aat gac agc tcc 544 Glu Val Gln Gln Cys Phe Tyr Gln Gly Phe Ile ArgAsn Asp Ser Ser 140 145 150 tcc tct gtc gct gtg tct acg tgt gct ggc ttgtca ggt tta ata agg 592 Ser Ser Val Ala Val Ser Thr Cys Ala Gly Leu SerGly Leu Ile Arg 155 160 165 170 aca cga aaa aat gaa ttc ctc atc tcg ccatta cct cag ctt ctg gcc 640 Thr Arg Lys Asn Glu Phe Leu Ile Ser Pro LeuPro Gln Leu Leu Ala 175 180 185 cag gaa cac aac tac agc tcc cct gcg ggtcac cat cct cac gta ctg 688 Gln Glu His Asn Tyr Ser Ser Pro Ala Gly HisHis Pro His Val Leu 190 195 200 tac aaa agg aca gca gag gag aag atc cagcgg tac cgt ggc tac ccc 736 Tyr Lys Arg Thr Ala Glu Glu Lys Ile Gln ArgTyr Arg Gly Tyr Pro 205 210 215 ggc tct ggc cgg aat tat cct ggt tac tcccca agt cac att ccc cat 784 Gly Ser Gly Arg Asn Tyr Pro Gly Tyr Ser ProSer His Ile Pro His 220 225 230 gca tct cag agt cga gag aca gag tat caccat cga agg ttg caa aag 832 Ala Ser Gln Ser Arg Glu Thr Glu Tyr His HisArg Arg Leu Gln Lys 235 240 245 250 cag cat ttt tgt gga cga cgc aag aaatat gct ccc aag cct ccc aca 880 Gln His Phe Cys Gly Arg Arg Lys Lys TyrAla Pro Lys Pro Pro Thr 255 260 265 gag gac acc tat cta agg ttt gat gaatat ggg agc tct ggg cga ccc 928 Glu Asp Thr Tyr Leu Arg Phe Asp Glu TyrGly Ser Ser Gly Arg Pro 270 275 280 aga aga tca gct gga aaa tca caa aagggc ctc aat gtg gaa acc ctc 976 Arg Arg Ser Ala Gly Lys Ser Gln Lys GlyLeu Asn Val Glu Thr Leu 285 290 295 gtg gtg gca gac aag aaa atg gtg gaaaag cat ggc aag gga aat gtc 1024 Val Val Ala Asp Lys Lys Met Val Glu LysHis Gly Lys Gly Asn Val 300 305 310 acc aca tac att ctc aca gta atg aaggtt tct ggc cta ttt aaa gat 1072 Thr Thr Tyr Ile Leu Thr Val Met Lys ValSer Gly Leu Phe Lys Asp 315 320 325 330 ggg act att gga agt gac ata aacgtg gtt gtg gtg agc cta att ctt 1120 Gly Thr Ile Gly Ser Asp Ile Asn ValVal Val Val Ser Leu Ile Leu 335 340 345 ctg gaa caa gaa cct gga gga ttattg atc aac cat cat gca gac cag 1168 Leu Glu Gln Glu Pro Gly Gly Leu LeuIle Asn His His Ala Asp Gln 350 355 360 tct ctg aat agt ttt tgt caa tggcag tct gcc ctc att gga aag aat 1216 Ser Leu Asn Ser Phe Cys Gln Trp GlnSer Ala Leu Ile Gly Lys Asn 365 370 375 ggc aag aga cat gat cat gcc atctta cta aca gga ttt gat att tgt 1264 Gly Lys Arg His Asp His Ala Ile LeuLeu Thr Gly Phe Asp Ile Cys 380 385 390 tct tgg aag aat gaa cca tgt gacact cta ggg ttt gcc ccc acc agt 1312 Ser Trp Lys Asn Glu Pro Cys Asp ThrLeu Gly Phe Ala Pro Thr Ser 395 400 405 410 gga atg tgc tct aag tac cgaagt tgt acc atc aat gag gac aca gga 1360 Gly Met Cys Ser Lys Tyr Arg SerCys Thr Ile Asn Glu Asp Thr Gly 415 420 425 ctt ggc ctt gcc ttc acc atcgct cat gag tca ggg cac aac ttt ggt 1408 Leu Gly Leu Ala Phe Thr Ile AlaHis Glu Ser Gly His Asn Phe Gly 430 435 440 atg att cac gac gga gaa gggaat ccc tgc aga aag gct gaa ggc aat 1456 Met Ile His Asp Gly Glu Gly AsnPro Cys Arg Lys Ala Glu Gly Asn 445 450 455 atc atg tct ccc aca ctg accgga aac aat gga gtg ttt tca tgg tct 1504 Ile Met Ser Pro Thr Leu Thr GlyAsn Asn Gly Val Phe Ser Trp Ser 460 465 470 tcc tgc agc cgc cag tat ctcaag aaa ttc ctc agc aca cct cag gcg 1552 Ser Cys Ser Arg Gln Tyr Leu LysLys Phe Leu Ser Thr Pro Gln Ala 475 480 485 490 ggg tgt cta gtg gat gagccc aag caa gca gga cag tat aaa tat ccg 1600 Gly Cys Leu Val Asp Glu ProLys Gln Ala Gly Gln Tyr Lys Tyr Pro 495 500 505 gac aaa cta cca gga cagatt tat gat gct gac aca cag tgt aaa tgg 1648 Asp Lys Leu Pro Gly Gln IleTyr Asp Ala Asp Thr Gln Cys Lys Trp 510 515 520 caa ttt gga gca aaa gccaag tta tgc agc ctt ggt ttt gtg aag gat 1696 Gln Phe Gly Ala Lys Ala LysLeu Cys Ser Leu Gly Phe Val Lys Asp 525 530 535 att tgc aaa tca ctt tggtgc cac cga gta ggc cac agg tgt gag acc 1744 Ile Cys Lys Ser Leu Trp CysHis Arg Val Gly His Arg Cys Glu Thr 540 545 550 aag ttt atg ccc gca gcagaa ggg acc gtt tgt ggc ttg agt atg tgg 1792 Lys Phe Met Pro Ala Ala GluGly Thr Val Cys Gly Leu Ser Met Trp 555 560 565 570 tgt cgg caa ggc cagtgc gta aag ttt ggg gag ctc ggg ccc cgg ccc 1840 Cys Arg Gln Gly Gln CysVal Lys Phe Gly Glu Leu Gly Pro Arg Pro 575 580 585 atc cac ggc cag tggtcc gcc tgg tcg aag tgg tca gaa tgt tcc cgg 1888 Ile His Gly Gln Trp SerAla Trp Ser Lys Trp Ser Glu Cys Ser Arg 590 595 600 aca tgt ggt gga ggagtc aag ttc cag gag aga cac tgc aat aac ccc 1936 Thr Cys Gly Gly Gly ValLys Phe Gln Glu Arg His Cys Asn Asn Pro 605 610 615 aag cct cag tat ggtggc ata ttc tgt cca ggt tct agc cgt att tat 1984 Lys Pro Gln Tyr Gly GlyIle Phe Cys Pro Gly Ser Ser Arg Ile Tyr 620 625 630 cag ctg tgc aat attaac cct tgc aat gaa aat agc ttg gat ttt cgg 2032 Gln Leu Cys Asn Ile AsnPro Cys Asn Glu Asn Ser Leu Asp Phe Arg 635 640 645 650 gct caa cag tgtgca gaa tat aac agc aaa cct ttc cgt gga tgg ttc 2080 Ala Gln Gln Cys AlaGlu Tyr Asn Ser Lys Pro Phe Arg Gly Trp Phe 655 660 665 tac cag tgg aaaccc tat aca aaa gtg gaa gag gaa gat cga tgc aaa 2128 Tyr Gln Trp Lys ProTyr Thr Lys Val Glu Glu Glu Asp Arg Cys Lys 670 675 680 ctg tac tgc aaggct gag aac ttt gaa ttt ttt ttt gca atg tcc ggc 2176 Leu Tyr Cys Lys AlaGlu Asn Phe Glu Phe Phe Phe Ala Met Ser Gly 685 690 695 aaa gtg aaa gatgga act ccc tgc tcc cca aac aaa aat gat gtt tgt 2224 Lys Val Lys Asp GlyThr Pro Cys Ser Pro Asn Lys Asn Asp Val Cys 700 705 710 att gac ggg gtttgt gaa cta gtg gga tgt gat cat gaa cta ggc tct 2272 Ile Asp Gly Val CysGlu Leu Val Gly Cys Asp His Glu Leu Gly Ser 715 720 725 730 aaa gca gtttca gat gct tgt ggc gtt tgc aaa ggt gat aat tca act 2320 Lys Ala Val SerAsp Ala Cys Gly Val Cys Lys Gly Asp Asn Ser Thr 735 740 745 tgc aag ttttat aaa ggc ctg tac ctc aac cag cat aaa gca aat gaa 2368 Cys Lys Phe TyrLys Gly Leu Tyr Leu Asn Gln His Lys Ala Asn Glu 750 755 760 tat tat ccggtg gtc ctc att cca gct ggc gcc cga agc atc gaa atc 2416 Tyr Tyr Pro ValVal Leu Ile Pro Ala Gly Ala Arg Ser Ile Glu Ile 765 770 775 cag gag ctgcag gtt tcc tcc agt tac ctc gca gtt cga agc ctc agt 2464 Gln Glu Leu GlnVal Ser Ser Ser Tyr Leu Ala Val Arg Ser Leu Ser 780 785 790 caa aag tattac ctc acc ggg ggc tgg agc atc gac tgg cct ggg gag 2512 Gln Lys Tyr TyrLeu Thr Gly Gly Trp Ser Ile Asp Trp Pro Gly Glu 795 800 805 810 ttc cccttc gct ggg acc acg ttt gaa tac cag cgc tct ttc aac cgc 2560 Phe Pro PheAla Gly Thr Thr Phe Glu Tyr Gln Arg Ser Phe Asn Arg 815 820 825 ccg gaacgt ctg tac gcg cca ggg ccc aca aat gag acg ctg gtc ttt 2608 Pro Glu ArgLeu Tyr Ala Pro Gly Pro Thr Asn Glu Thr Leu Val Phe 830 835 840 gaa attctg atg caa ggc aaa aat cca ggg ata gct tgg aag tat gca 2656 Glu Ile LeuMet Gln Gly Lys Asn Pro Gly Ile Ala Trp Lys Tyr Ala 845 850 855 ctt cccaag gtc atg aat gga act cca cca gcc aca aaa aga cct gcc 2704 Leu Pro LysVal Met Asn Gly Thr Pro Pro Ala Thr Lys Arg Pro Ala 860 865 870 tat acctgg agt atc gtg cag tca gag tgc tcc gtc tcc tgt ggt gga 2752 Tyr Thr TrpSer Ile Val Gln Ser Glu Cys Ser Val Ser Cys Gly Gly 875 880 885 890 ggttac ata aat gta aag gcc att tgc ttg cga gat caa aat act caa 2800 Gly TyrIle Asn Val Lys Ala Ile Cys Leu Arg Asp Gln Asn Thr Gln 895 900 905 gtcaat tcc tca ttc tgc agt gca aaa acc aag cca gta act gag ccc 2848 Val AsnSer Ser Phe Cys Ser Ala Lys Thr Lys Pro Val Thr Glu Pro 910 915 920 aaaatc tgc aac gct ttc tcc tgc ccg gct tac tgg atg cca ggt gaa 2896 Lys IleCys Asn Ala Phe Ser Cys Pro Ala Tyr Trp Met Pro Gly Glu 925 930 935 tggagt aca tgc agc aag tcc tgt gct gga ggc cag cag agc cga aag 2944 Trp SerThr Cys Ser Lys Ser Cys Ala Gly Gly Gln Gln Ser Arg Lys 940 945 950 atccag tgt gtg caa aag aag ccc ttc caa aag gag gaa gca gtg ttg 2992 Ile GlnCys Val Gln Lys Lys Pro Phe Gln Lys Glu Glu Ala Val Leu 955 960 965 970cat tct ctc tgt cca gta agc aca ccc act cag gtc caa gcc tgc aac 3040 HisSer Leu Cys Pro Val Ser Thr Pro Thr Gln Val Gln Ala Cys Asn 975 980 985agc cat gcc tgc cct cca caa tgg agc ctt gga ccc tgg tct cag tgt 3088 SerHis Ala Cys Pro Pro Gln Trp Ser Leu Gly Pro Trp Ser Gln Cys 990 995 1000tcc aag acc tgt gga cga ggg gtg agg aag cgt gaa ctc ctc tgc aag 3136 SerLys Thr Cys Gly Arg Gly Val Arg Lys Arg Glu Leu Leu Cys Lys 1005 10101015 ggc tct gcc gca gaa acc ctc ccc gag agc cag tgt acc agt ctc ccc3184 Gly Ser Ala Ala Glu Thr Leu Pro Glu Ser Gln Cys Thr Ser Leu Pro1020 1025 1030 aga cct gag ctg cag gag ggc tgt gtg ctt gga cga tgt cccaag aac 3232 Arg Pro Glu Leu Gln Glu Gly Cys Val Leu Gly Arg Cys Pro LysAsn 1035 1040 1045 1050 agc cgg cta cag tgg gtc gct tct tcg tgg agc gaggta tgg att aga 3280 Ser Arg Leu Gln Trp Val Ala Ser Ser Trp Ser Glu ValTrp Ile Arg 1055 1060 1065 agt cac tgc tgg gtc agg aga ttg aga cca tcctgg cta aca cag tga 3328 Ser His Cys Trp Val Arg Arg Leu Arg Pro Ser TrpLeu Thr Gln * 1070 1075 1080 aaccctgtct ctactaaaaa tacaaaaaat tagccaggcaaggtggcagg cgcctgtagt 3388 ctgatctact ggggctgtag tctgatctac tggggctgttcttgggacat cgtcggg 3445 87 1081 PRT Homo sapiens 87 Met Glu Cys Ala LeuLeu Leu Ala Cys Ala Phe Pro Ala Ala Gly Ser 1 5 10 15 Gly Pro Pro ArgGly Leu Ala Gly Leu Gly Arg Val Ala Lys Ala Leu 20 25 30 Gln Leu Cys CysLeu Cys Cys Ala Ser Val Ala Ala Ala Leu Ala Ser 35 40 45 Asp Ser Ser SerGly Ala Ser Gly Leu Asn Asp Asp Tyr Val Phe Val 50 55 60 Thr Pro Val GluVal Asp Ser Ala Gly Ser Tyr Ile Ser His Asp Ile 65 70 75 80 Leu His AsnGly Arg Lys Lys Arg Ser Ala Gln Asn Ala Arg Ser Ser 85 90 95 Leu His TyrArg Phe Ser Ala Phe Gly Gln Glu Leu His Leu Glu Leu 100 105 110 Lys ProSer Ala Ile Leu Ser Ser His Phe Ile Val Gln Val Leu Gly 115 120 125 LysAsp Gly Ala Ser Glu Thr Gln Lys Pro Glu Val Gln Gln Cys Phe 130 135 140Tyr Gln Gly Phe Ile Arg Asn Asp Ser Ser Ser Ser Val Ala Val Ser 145 150155 160 Thr Cys Ala Gly Leu Ser Gly Leu Ile Arg Thr Arg Lys Asn Glu Phe165 170 175 Leu Ile Ser Pro Leu Pro Gln Leu Leu Ala Gln Glu His Asn TyrSer 180 185 190 Ser Pro Ala Gly His His Pro His Val Leu Tyr Lys Arg ThrAla Glu 195 200 205 Glu Lys Ile Gln Arg Tyr Arg Gly Tyr Pro Gly Ser GlyArg Asn Tyr 210 215 220 Pro Gly Tyr Ser Pro Ser His Ile Pro His Ala SerGln Ser Arg Glu 225 230 235 240 Thr Glu Tyr His His Arg Arg Leu Gln LysGln His Phe Cys Gly Arg 245 250 255 Arg Lys Lys Tyr Ala Pro Lys Pro ProThr Glu Asp Thr Tyr Leu Arg 260 265 270 Phe Asp Glu Tyr Gly Ser Ser GlyArg Pro Arg Arg Ser Ala Gly Lys 275 280 285 Ser Gln Lys Gly Leu Asn ValGlu Thr Leu Val Val Ala Asp Lys Lys 290 295 300 Met Val Glu Lys His GlyLys Gly Asn Val Thr Thr Tyr Ile Leu Thr 305 310 315 320 Val Met Lys ValSer Gly Leu Phe Lys Asp Gly Thr Ile Gly Ser Asp 325 330 335 Ile Asn ValVal Val Val Ser Leu Ile Leu Leu Glu Gln Glu Pro Gly 340 345 350 Gly LeuLeu Ile Asn His His Ala Asp Gln Ser Leu Asn Ser Phe Cys 355 360 365 GlnTrp Gln Ser Ala Leu Ile Gly Lys Asn Gly Lys Arg His Asp His 370 375 380Ala Ile Leu Leu Thr Gly Phe Asp Ile Cys Ser Trp Lys Asn Glu Pro 385 390395 400 Cys Asp Thr Leu Gly Phe Ala Pro Thr Ser Gly Met Cys Ser Lys Tyr405 410 415 Arg Ser Cys Thr Ile Asn Glu Asp Thr Gly Leu Gly Leu Ala PheThr 420 425 430 Ile Ala His Glu Ser Gly His Asn Phe Gly Met Ile His AspGly Glu 435 440 445 Gly Asn Pro Cys Arg Lys Ala Glu Gly Asn Ile Met SerPro Thr Leu 450 455 460 Thr Gly Asn Asn Gly Val Phe Ser Trp Ser Ser CysSer Arg Gln Tyr 465 470 475 480 Leu Lys Lys Phe Leu Ser Thr Pro Gln AlaGly Cys Leu Val Asp Glu 485 490 495 Pro Lys Gln Ala Gly Gln Tyr Lys TyrPro Asp Lys Leu Pro Gly Gln 500 505 510 Ile Tyr Asp Ala Asp Thr Gln CysLys Trp Gln Phe Gly Ala Lys Ala 515 520 525 Lys Leu Cys Ser Leu Gly PheVal Lys Asp Ile Cys Lys Ser Leu Trp 530 535 540 Cys His Arg Val Gly HisArg Cys Glu Thr Lys Phe Met Pro Ala Ala 545 550 555 560 Glu Gly Thr ValCys Gly Leu Ser Met Trp Cys Arg Gln Gly Gln Cys 565 570 575 Val Lys PheGly Glu Leu Gly Pro Arg Pro Ile His Gly Gln Trp Ser 580 585 590 Ala TrpSer Lys Trp Ser Glu Cys Ser Arg Thr Cys Gly Gly Gly Val 595 600 605 LysPhe Gln Glu Arg His Cys Asn Asn Pro Lys Pro Gln Tyr Gly Gly 610 615 620Ile Phe Cys Pro Gly Ser Ser Arg Ile Tyr Gln Leu Cys Asn Ile Asn 625 630635 640 Pro Cys Asn Glu Asn Ser Leu Asp Phe Arg Ala Gln Gln Cys Ala Glu645 650 655 Tyr Asn Ser Lys Pro Phe Arg Gly Trp Phe Tyr Gln Trp Lys ProTyr 660 665 670 Thr Lys Val Glu Glu Glu Asp Arg Cys Lys Leu Tyr Cys LysAla Glu 675 680 685 Asn Phe Glu Phe Phe Phe Ala Met Ser Gly Lys Val LysAsp Gly Thr 690 695 700 Pro Cys Ser Pro Asn Lys Asn Asp Val Cys Ile AspGly Val Cys Glu 705 710 715 720 Leu Val Gly Cys Asp His Glu Leu Gly SerLys Ala Val Ser Asp Ala 725 730 735 Cys Gly Val Cys Lys Gly Asp Asn SerThr Cys Lys Phe Tyr Lys Gly 740 745 750 Leu Tyr Leu Asn Gln His Lys AlaAsn Glu Tyr Tyr Pro Val Val Leu 755 760 765 Ile Pro Ala Gly Ala Arg SerIle Glu Ile Gln Glu Leu Gln Val Ser 770 775 780 Ser Ser Tyr Leu Ala ValArg Ser Leu Ser Gln Lys Tyr Tyr Leu Thr 785 790 795 800 Gly Gly Trp SerIle Asp Trp Pro Gly Glu Phe Pro Phe Ala Gly Thr 805 810 815 Thr Phe GluTyr Gln Arg Ser Phe Asn Arg Pro Glu Arg Leu Tyr Ala 820 825 830 Pro GlyPro Thr Asn Glu Thr Leu Val Phe Glu Ile Leu Met Gln Gly 835 840 845 LysAsn Pro Gly Ile Ala Trp Lys Tyr Ala Leu Pro Lys Val Met Asn 850 855 860Gly Thr Pro Pro Ala Thr Lys Arg Pro Ala Tyr Thr Trp Ser Ile Val 865 870875 880 Gln Ser Glu Cys Ser Val Ser Cys Gly Gly Gly Tyr Ile Asn Val Lys885 890 895 Ala Ile Cys Leu Arg Asp Gln Asn Thr Gln Val Asn Ser Ser PheCys 900 905 910 Ser Ala Lys Thr Lys Pro Val Thr Glu Pro Lys Ile Cys AsnAla Phe 915 920 925 Ser Cys Pro Ala Tyr Trp Met Pro Gly Glu Trp Ser ThrCys Ser Lys 930 935 940 Ser Cys Ala Gly Gly Gln Gln Ser Arg Lys Ile GlnCys Val Gln Lys 945 950 955 960 Lys Pro Phe Gln Lys Glu Glu Ala Val LeuHis Ser Leu Cys Pro Val 965 970 975 Ser Thr Pro Thr Gln Val Gln Ala CysAsn Ser His Ala Cys Pro Pro 980 985 990 Gln Trp Ser Leu Gly Pro Trp SerGln Cys Ser Lys Thr Cys Gly Arg 995 1000 1005 Gly Val Arg Lys Arg GluLeu Leu Cys Lys Gly Ser Ala Ala Glu Thr 1010 1015 1020 Leu Pro Glu SerGln Cys Thr Ser Leu Pro Arg Pro Glu Leu Gln Glu 1025 1030 1035 1040 GlyCys Val Leu Gly Arg Cys Pro Lys Asn Ser Arg Leu Gln Trp Val 1045 10501055 Ala Ser Ser Trp Ser Glu Val Trp Ile Arg Ser His Cys Trp Val Arg1060 1065 1070 Arg Leu Arg Pro Ser Trp Leu Thr Gln 1075 1080 88 3246 DNAHomo sapiens CDS (1)...(3246) 88 atg gag tgc gcc ctc ctg ctc gcg tgt gccttc ccg gct gcg ggt tcg 48 Met Glu Cys Ala Leu Leu Leu Ala Cys Ala PhePro Ala Ala Gly Ser 1 5 10 15 ggc ccg ccg agg ggc ctg gcg gga ctg gggcgc gtg gcc aag gcg ctc 96 Gly Pro Pro Arg Gly Leu Ala Gly Leu Gly ArgVal Ala Lys Ala Leu 20 25 30 cag ctg tgc tgc ctc tgc tgt gcg tcg gtc gccgcg gcc tta gcc agt 144 Gln Leu Cys Cys Leu Cys Cys Ala Ser Val Ala AlaAla Leu Ala Ser 35 40 45 gac agc agc agc ggc gcc agc gga tta aat gat gattac gtc ttt gtc 192 Asp Ser Ser Ser Gly Ala Ser Gly Leu Asn Asp Asp TyrVal Phe Val 50 55 60 acg cca gta gaa gta gac tca gcc ggg tca tat att tcacac gac att 240 Thr Pro Val Glu Val Asp Ser Ala Gly Ser Tyr Ile Ser HisAsp Ile 65 70 75 80 ttg cac aac ggc agg aaa aag cga tcg gcg cag aat gccaga agc tcc 288 Leu His Asn Gly Arg Lys Lys Arg Ser Ala Gln Asn Ala ArgSer Ser 85 90 95 ctg cac tac cga ttt tca gca ttt gga cag gaa ctg cac ttagaa ctt 336 Leu His Tyr Arg Phe Ser Ala Phe Gly Gln Glu Leu His Leu GluLeu 100 105 110 aag ccc tcg gcg att ttg agc agt cac ttt att gtc cag gtactt gga 384 Lys Pro Ser Ala Ile Leu Ser Ser His Phe Ile Val Gln Val LeuGly 115 120 125 aaa gat ggt gct tca gag act cag aaa ccc gag gtg cag caatgc ttc 432 Lys Asp Gly Ala Ser Glu Thr Gln Lys Pro Glu Val Gln Gln CysPhe 130 135 140 tat cag gga ttt atc aga aat gac agc tcc tcc tct gtc gctgtg tct 480 Tyr Gln Gly Phe Ile Arg Asn Asp Ser Ser Ser Ser Val Ala ValSer 145 150 155 160 acg tgt gct ggc ttg tca ggt tta ata agg aca cga aaaaat gaa ttc 528 Thr Cys Ala Gly Leu Ser Gly Leu Ile Arg Thr Arg Lys AsnGlu Phe 165 170 175 ctc atc tcg cca tta cct cag ctt ctg gcc cag gaa cacaac tac agc 576 Leu Ile Ser Pro Leu Pro Gln Leu Leu Ala Gln Glu His AsnTyr Ser 180 185 190 tcc cct gcg ggt cac cat cct cac gta ctg tac aaa aggaca gca gag 624 Ser Pro Ala Gly His His Pro His Val Leu Tyr Lys Arg ThrAla Glu 195 200 205 gag aag atc cag cgg tac cgt ggc tac ccc ggc tct ggccgg aat tat 672 Glu Lys Ile Gln Arg Tyr Arg Gly Tyr Pro Gly Ser Gly ArgAsn Tyr 210 215 220 cct ggt tac tcc cca agt cac att ccc cat gca tct cagagt cga gag 720 Pro Gly Tyr Ser Pro Ser His Ile Pro His Ala Ser Gln SerArg Glu 225 230 235 240 aca gag tat cac cat cga agg ttg caa aag cag catttt tgt gga cga 768 Thr Glu Tyr His His Arg Arg Leu Gln Lys Gln His PheCys Gly Arg 245 250 255 cgc aag aaa tat gct ccc aag cct ccc aca gag gacacc tat cta agg 816 Arg Lys Lys Tyr Ala Pro Lys Pro Pro Thr Glu Asp ThrTyr Leu Arg 260 265 270 ttt gat gaa tat ggg agc tct ggg cga ccc aga agatca gct gga aaa 864 Phe Asp Glu Tyr Gly Ser Ser Gly Arg Pro Arg Arg SerAla Gly Lys 275 280 285 tca caa aag ggc ctc aat gtg gaa acc ctc gtg gtggca gac aag aaa 912 Ser Gln Lys Gly Leu Asn Val Glu Thr Leu Val Val AlaAsp Lys Lys 290 295 300 atg gtg gaa aag cat ggc aag gga aat gtc acc acatac att ctc aca 960 Met Val Glu Lys His Gly Lys Gly Asn Val Thr Thr TyrIle Leu Thr 305 310 315 320 gta atg aag gtt tct ggc cta ttt aaa gat gggact att gga agt gac 1008 Val Met Lys Val Ser Gly Leu Phe Lys Asp Gly ThrIle Gly Ser Asp 325 330 335 ata aac gtg gtt gtg gtg agc cta att ctt ctggaa caa gaa cct gga 1056 Ile Asn Val Val Val Val Ser Leu Ile Leu Leu GluGln Glu Pro Gly 340 345 350 gga tta ttg atc aac cat cat gca gac cag tctctg aat agt ttt tgt 1104 Gly Leu Leu Ile Asn His His Ala Asp Gln Ser LeuAsn Ser Phe Cys 355 360 365 caa tgg cag tct gcc ctc att gga aag aat ggcaag aga cat gat cat 1152 Gln Trp Gln Ser Ala Leu Ile Gly Lys Asn Gly LysArg His Asp His 370 375 380 gcc atc tta cta aca gga ttt gat att tgt tcttgg aag aat gaa cca 1200 Ala Ile Leu Leu Thr Gly Phe Asp Ile Cys Ser TrpLys Asn Glu Pro 385 390 395 400 tgt gac act cta ggg ttt gcc ccc acc agtgga atg tgc tct aag tac 1248 Cys Asp Thr Leu Gly Phe Ala Pro Thr Ser GlyMet Cys Ser Lys Tyr 405 410 415 cga agt tgt acc atc aat gag gac aca ggactt ggc ctt gcc ttc acc 1296 Arg Ser Cys Thr Ile Asn Glu Asp Thr Gly LeuGly Leu Ala Phe Thr 420 425 430 atc gct cat gag tca ggg cac aac ttt ggtatg att cac gac gga gaa 1344 Ile Ala His Glu Ser Gly His Asn Phe Gly MetIle His Asp Gly Glu 435 440 445 ggg aat ccc tgc aga aag gct gaa ggc aatatc atg tct ccc aca ctg 1392 Gly Asn Pro Cys Arg Lys Ala Glu Gly Asn IleMet Ser Pro Thr Leu 450 455 460 acc gga aac aat gga gtg ttt tca tgg tcttcc tgc agc cgc cag tat 1440 Thr Gly Asn Asn Gly Val Phe Ser Trp Ser SerCys Ser Arg Gln Tyr 465 470 475 480 ctc aag aaa ttc ctc agc aca cct caggcg ggg tgt cta gtg gat gag 1488 Leu Lys Lys Phe Leu Ser Thr Pro Gln AlaGly Cys Leu Val Asp Glu 485 490 495 ccc aag caa gca gga cag tat aaa tatccg gac aaa cta cca gga cag 1536 Pro Lys Gln Ala Gly Gln Tyr Lys Tyr ProAsp Lys Leu Pro Gly Gln 500 505 510 att tat gat gct gac aca cag tgt aaatgg caa ttt gga gca aaa gcc 1584 Ile Tyr Asp Ala Asp Thr Gln Cys Lys TrpGln Phe Gly Ala Lys Ala 515 520 525 aag tta tgc agc ctt ggt ttt gtg aaggat att tgc aaa tca ctt tgg 1632 Lys Leu Cys Ser Leu Gly Phe Val Lys AspIle Cys Lys Ser Leu Trp 530 535 540 tgc cac cga gta ggc cac agg tgt gagacc aag ttt atg ccc gca gca 1680 Cys His Arg Val Gly His Arg Cys Glu ThrLys Phe Met Pro Ala Ala 545 550 555 560 gaa ggg acc gtt tgt ggc ttg agtatg tgg tgt cgg caa ggc cag tgc 1728 Glu Gly Thr Val Cys Gly Leu Ser MetTrp Cys Arg Gln Gly Gln Cys 565 570 575 gta aag ttt ggg gag ctc ggg ccccgg ccc atc cac ggc cag tgg tcc 1776 Val Lys Phe Gly Glu Leu Gly Pro ArgPro Ile His Gly Gln Trp Ser 580 585 590 gcc tgg tcg aag tgg tca gaa tgttcc cgg aca tgt ggt gga gga gtc 1824 Ala Trp Ser Lys Trp Ser Glu Cys SerArg Thr Cys Gly Gly Gly Val 595 600 605 aag ttc cag gag aga cac tgc aataac ccc aag cct cag tat ggt ggc 1872 Lys Phe Gln Glu Arg His Cys Asn AsnPro Lys Pro Gln Tyr Gly Gly 610 615 620 ata ttc tgt cca ggt tct agc cgtatt tat cag ctg tgc aat att aac 1920 Ile Phe Cys Pro Gly Ser Ser Arg IleTyr Gln Leu Cys Asn Ile Asn 625 630 635 640 cct tgc aat gaa aat agc ttggat ttt cgg gct caa cag tgt gca gaa 1968 Pro Cys Asn Glu Asn Ser Leu AspPhe Arg Ala Gln Gln Cys Ala Glu 645 650 655 tat aac agc aaa cct ttc cgtgga tgg ttc tac cag tgg aaa ccc tat 2016 Tyr Asn Ser Lys Pro Phe Arg GlyTrp Phe Tyr Gln Trp Lys Pro Tyr 660 665 670 aca aaa gtg gaa gag gaa gatcga tgc aaa ctg tac tgc aag gct gag 2064 Thr Lys Val Glu Glu Glu Asp ArgCys Lys Leu Tyr Cys Lys Ala Glu 675 680 685 aac ttt gaa ttt ttt ttt gcaatg tcc ggc aaa gtg aaa gat gga act 2112 Asn Phe Glu Phe Phe Phe Ala MetSer Gly Lys Val Lys Asp Gly Thr 690 695 700 ccc tgc tcc cca aac aaa aatgat gtt tgt att gac ggg gtt tgt gaa 2160 Pro Cys Ser Pro Asn Lys Asn AspVal Cys Ile Asp Gly Val Cys Glu 705 710 715 720 cta gtg gga tgt gat catgaa cta ggc tct aaa gca gtt tca gat gct 2208 Leu Val Gly Cys Asp His GluLeu Gly Ser Lys Ala Val Ser Asp Ala 725 730 735 tgt ggc gtt tgc aaa ggtgat aat tca act tgc aag ttt tat aaa ggc 2256 Cys Gly Val Cys Lys Gly AspAsn Ser Thr Cys Lys Phe Tyr Lys Gly 740 745 750 ctg tac ctc aac cag cataaa gca aat gaa tat tat ccg gtg gtc ctc 2304 Leu Tyr Leu Asn Gln His LysAla Asn Glu Tyr Tyr Pro Val Val Leu 755 760 765 att cca gct ggc gcc cgaagc atc gaa atc cag gag ctg cag gtt tcc 2352 Ile Pro Ala Gly Ala Arg SerIle Glu Ile Gln Glu Leu Gln Val Ser 770 775 780 tcc agt tac ctc gca gttcga agc ctc agt caa aag tat tac ctc acc 2400 Ser Ser Tyr Leu Ala Val ArgSer Leu Ser Gln Lys Tyr Tyr Leu Thr 785 790 795 800 ggg ggc tgg agc atcgac tgg cct ggg gag ttc ccc ttc gct ggg acc 2448 Gly Gly Trp Ser Ile AspTrp Pro Gly Glu Phe Pro Phe Ala Gly Thr 805 810 815 acg ttt gaa tac cagcgc tct ttc aac cgc ccg gaa cgt ctg tac gcg 2496 Thr Phe Glu Tyr Gln ArgSer Phe Asn Arg Pro Glu Arg Leu Tyr Ala 820 825 830 cca ggg ccc aca aatgag acg ctg gtc ttt gaa att ctg atg caa ggc 2544 Pro Gly Pro Thr Asn GluThr Leu Val Phe Glu Ile Leu Met Gln Gly 835 840 845 aaa aat cca ggg atagct tgg aag tat gca ctt ccc aag gtc atg aat 2592 Lys Asn Pro Gly Ile AlaTrp Lys Tyr Ala Leu Pro Lys Val Met Asn 850 855 860 gga act cca cca gccaca aaa aga cct gcc tat acc tgg agt atc gtg 2640 Gly Thr Pro Pro Ala ThrLys Arg Pro Ala Tyr Thr Trp Ser Ile Val 865 870 875 880 cag tca gag tgctcc gtc tcc tgt ggt gga ggt tac ata aat gta aag 2688 Gln Ser Glu Cys SerVal Ser Cys Gly Gly Gly Tyr Ile Asn Val Lys 885 890 895 gcc att tgc ttgcga gat caa aat act caa gtc aat tcc tca ttc tgc 2736 Ala Ile Cys Leu ArgAsp Gln Asn Thr Gln Val Asn Ser Ser Phe Cys 900 905 910 agt gca aaa accaag cca gta act gag ccc aaa atc tgc aac gct ttc 2784 Ser Ala Lys Thr LysPro Val Thr Glu Pro Lys Ile Cys Asn Ala Phe 915 920 925 tcc tgc ccg gcttac tgg atg cca ggt gaa tgg agt aca tgc agc aag 2832 Ser Cys Pro Ala TyrTrp Met Pro Gly Glu Trp Ser Thr Cys Ser Lys 930 935 940 tcc tgt gct ggaggc cag cag agc cga aag atc cag tgt gtg caa aag 2880 Ser Cys Ala Gly GlyGln Gln Ser Arg Lys Ile Gln Cys Val Gln Lys 945 950 955 960 aag ccc ttccaa aag gag gaa gca gtg ttg cat tct ctc tgt cca gta 2928 Lys Pro Phe GlnLys Glu Glu Ala Val Leu His Ser Leu Cys Pro Val 965 970 975 agc aca cccact cag gtc caa gcc tgc aac agc cat gcc tgc cct cca 2976 Ser Thr Pro ThrGln Val Gln Ala Cys Asn Ser His Ala Cys Pro Pro 980 985 990 caa tgg agcctt gga ccc tgg tct cag tgt tcc aag acc tgt gga cga 3024 Gln Trp Ser LeuGly Pro Trp Ser Gln Cys Ser Lys Thr Cys Gly Arg 995 1000 1005 ggg gtgagg aag cgt gaa ctc ctc tgc aag ggc tct gcc gca gaa acc 3072 Gly Val ArgLys Arg Glu Leu Leu Cys Lys Gly Ser Ala Ala Glu Thr 1010 1015 1020 ctcccc gag agc cag tgt acc agt ctc ccc aga cct gag ctg cag gag 3120 Leu ProGlu Ser Gln Cys Thr Ser Leu Pro Arg Pro Glu Leu Gln Glu 1025 1030 10351040 ggc tgt gtg ctt gga cga tgt ccc aag aac agc cgg cta cag tgg gtc3168 Gly Cys Val Leu Gly Arg Cys Pro Lys Asn Ser Arg Leu Gln Trp Val1045 1050 1055 gct tct tcg tgg agc gag gta tgg att aga agt cac tgc tgggtc agg 3216 Ala Ser Ser Trp Ser Glu Val Trp Ile Arg Ser His Cys Trp ValArg 1060 1065 1070 aga ttg aga cca tcc tgg cta aca cag tga 3246 Arg LeuArg Pro Ser Trp Leu Thr Gln * 1075 1080 89 119 PRT Artificial SequenceConsensus amino acid sequence 89 His Leu Glu Lys Asn Arg Ser Leu Leu AlaPro Asp Phe Thr Val Thr 1 5 10 15 Thr Tyr Asp Glu Asp Gly Thr Leu ValThr Glu Glu Pro Leu Ile Gln 20 25 30 Asp Asp His Cys Tyr Tyr Gln Gly TyrVal Glu Gly Tyr Pro Asn Ser 35 40 45 Ala Val Ser Leu Ser Thr Cys Ser GlyGly Leu Arg Gly Ile Leu Gln 50 55 60 Leu Glu Asn Leu Ser Tyr Gly Ile GluPro Leu Glu Ser Ser Asp Gly 65 70 75 80 Phe Glu His Ile Ile Tyr Gln IleGlu Asn Asp Lys Thr Glu Pro Ser 85 90 95 Pro Cys Gly Glu Cys Gly Ser LeuSer Thr Ser Thr Asp Ser Ser Tyr 100 105 110 Gly Ile Arg Ser Ala Ser Pro115 90 187 PRT Artificial Sequence Consensus amino acid sequence 90 TyrGly Ser Asp Leu Asn Lys Ile Arg Gln Arg Val His Gln Ile Val 1 5 10 15Asn Leu Val Asn Glu Ile Tyr Arg Pro Gln Leu Asn Ile Arg Val Val 20 25 30Leu Val Gly Leu Glu Ile Trp Ser Asp Gly Asp Lys Ile Asn Val Gln 35 40 45Ser Asp Ala Asn Asp Thr Leu His Ser Phe Gly Glu Trp Arg Glu Thr 50 55 60Asp Leu Leu Lys Arg Lys Ser His Asp Asn Ala Gln Leu Leu Thr Gly 65 70 7580 Ile Asp Phe Asp Gly Asn Thr Ile Gly Ala Ala Tyr Val Gly Gly Met 85 9095 Cys Ser Pro Lys Arg Ser Val Gly Val Val Gln Asp His Ser Pro Ile 100105 110 Val Leu Leu Val Ala Val Thr Met Ala His Glu Leu Gly His Asn Leu115 120 125 Gly Met Thr His Asp Asp Lys Asn Lys Asp Gly Cys Thr Cys GluGly 130 135 140 Gly Gly Ser Cys Ile Met Asn Pro Val Ala Ser Ser Ser ProSer Lys 145 150 155 160 Lys Lys Phe Ser Asn Cys Ser Lys Asp Asp Tyr GlnLys Phe Leu Thr 165 170 175 Lys Gln Lys Pro Gln Cys Leu Leu Asn Lys Pro180 185 91 1311 PRT Homo sapiens 91 Met Arg Leu Leu Leu Leu Val Pro LeuLeu Leu Ala Pro Ala Pro Gly 1 5 10 15 Ser Ser Ala Pro Lys Val Arg ArgGln Ser Asp Thr Trp Gly Pro Trp 20 25 30 Ser Gln Trp Ser Pro Cys Ser ArgThr Cys Gly Gly Gly Val Ser Phe 35 40 45 Arg Glu Arg Pro Cys Tyr Ser GlnArg Arg Asp Gly Gly Ser Ser Cys 50 55 60 Val Gly Pro Ala Arg Ser His ArgSer Cys Arg Thr Glu Ser Cys Pro 65 70 75 80 Asp Gly Ala Arg Asp Phe ArgAla Glu Gln Cys Ala Glu Phe Asp Gly 85 90 95 Ala Glu Phe Gln Gly Arg ArgTyr Arg Trp Leu Pro Tyr Tyr Ser Ala 100 105 110 Pro Asn Lys Cys Glu LeuAsn Cys Ile Pro Lys Gly Glu Asn Phe Tyr 115 120 125 Tyr Lys His Arg GluAla Val Val Asp Gly Thr Pro Cys Glu Pro Gly 130 135 140 Lys Arg Asp ValCys Val Asp Gly Ser Cys Arg Val Val Gly Cys Asp 145 150 155 160 His GluLeu Asp Ser Ser Lys Gln Glu Asp Lys Cys Leu Arg Cys Gly 165 170 175 GlyAsp Gly Thr Cys Tyr Pro Val Ala Gly Thr Phe Asp Ala Asn Asp 180 185 190Leu Ser Arg Gly Tyr Asn Gln Ile Leu Ile Val Pro Met Gly Ala Thr 195 200205 Ser Ile Leu Ile Asp Glu Ala Ala Ala Ser Arg Asn Phe Leu Ala Val 210215 220 Lys Asn Val Arg Gly Glu Tyr Tyr Leu Asn Gly His Trp Thr Ile Glu225 230 235 240 Ala Ala Arg Ala Leu Pro Ala Ala Ser Thr Ile Leu His TyrGlu Arg 245 250 255 Gly Ala Glu Gly Asp Leu Ala Pro Glu Arg Leu His AlaArg Gly Pro 260 265 270 Thr Ser Glu Pro Leu Val Ile Glu Leu Ile Ser GlnGlu Pro Asn Pro 275 280 285 Gly Val His Tyr Glu Tyr His Leu Pro Leu ArgArg Pro Ser Pro Gly 290 295 300 Phe Ser Trp Ser His Gly Ser Trp Ser AspCys Ser Ala Glu Cys Gly 305 310 315 320 Gly Gly His Gln Ser Arg Leu ValPhe Cys Thr Ile Asp His Glu Ala 325 330 335 Tyr Pro Asp His Met Cys GlnArg Gln Pro Arg Pro Ala Asp Arg Arg 340 345 350 Ser Cys Asn Leu His ProCys Pro Glu Thr Lys Arg Thr Ser Tyr Leu 355 360 365 His Arg Pro Gly AlaTrp Arg Leu Ala Gly Ala Gln Arg Val Cys Gly 370 375 380 Asn Ser Trp LysAla Gly Pro Trp Ala Pro Cys Ser Ala Ser Cys Gly 385 390 395 400 Gly GlySer Gln Ser Arg Ser Val Tyr Cys Ile Ser Ser Asp Gly Ala 405 410 415 GlyIle Gln Glu Ala Val Glu Glu Ala Glu Cys Ala Gly Leu Pro Gly 420 425 430Lys Pro Pro Ala Ile Gln Ala Cys Asn Leu Gln Arg Cys Ala Ala Trp 435 440445 Ser Pro Glu Pro Trp Gly Glu Cys Ser Val Ser Cys Gly Val Gly Val 450455 460 Arg Lys Arg Ser Val Thr Cys Arg Gly Glu Arg Gly Ser Leu Leu His465 470 475 480 Thr Ala Ala Cys Ser Leu Glu Asp Arg Pro Pro Leu Thr GluPro Cys 485 490 495 Val His Glu Asp Cys Pro Leu Leu Ser Asp Gln Ala TrpHis Val Gly 500 505 510 Thr Trp Gly Leu Cys Ser Lys Ser Cys Ser Ser GlyThr Arg Arg Arg 515 520 525 Gln Val Ile Cys Ala Ile Gly Pro Pro Ser HisCys Gly Ser Leu Gln 530 535 540 His Ser Lys Pro Val Asp Val Glu Pro CysAsn Thr Gln Pro Cys His 545 550 555 560 Leu Pro Gln Glu Val Pro Ser MetGln Asp Val His Thr Pro Ala Ser 565 570 575 Asn Pro Trp Met Pro Leu GlyPro Gln Glu Ser Pro Ala Ser Ala Ala 580 585 590 Pro Ile Pro Ala Thr ProAla Val Gly Leu Arg Ala Pro Arg Leu Gln 595 600 605 Thr Gln Ser Ser ArgVal Leu Pro Arg Trp Pro His Gly Ile Ser Arg 610 615 620 Ala Ser Val AlaArg Leu Pro Trp Gly Pro Leu Ser Ala Glu Gln Val 625 630 635 640 His AsnThr His Gln Pro Gln Ala Gln Gln Asn Glu Pro Ser Glu Cys 645 650 655 ArgGly Asp Thr Tyr Leu Arg Phe Asp Glu Tyr Gly Ser Ser Gly Arg 660 665 670Pro Arg Arg Ser Ala Gly Lys Ser Gln Lys Gly Leu Asn Val Glu Thr 675 680685 Leu Val Val Ala Asp Lys Lys Met Val Glu Lys His Gly Lys Gly Ser 690695 700 Gln Phe Gly Cys Cys Tyr Asp Asn Val Ala Thr Ala Ala Gly Pro Leu705 710 715 720 Gly Glu Gly Cys Val Gly Gln Pro Ser His Ala Tyr Pro ValArg Cys 725 730 735 Leu Leu Pro Ser Ala His Gly Ser Cys Ala Asp Trp AlaAla Arg Trp 740 745 750 Tyr Phe Val Ala Ser Val Gly Gln Cys Asn Arg PheTrp Tyr Gly Gly 755 760 765 Cys His Gly Asn Ala Asn Asn Phe Ala Ser GluGln Glu Cys Met Ser 770 775 780 Ser Cys Gln Gly Ser Leu His Gly Pro ArgArg Pro Gln Pro Gly Ala 785 790 795 800 Ser Gly Arg Ser Thr His Thr AspGly Gly Gly Ser Ser Pro Ala Gly 805 810 815 Glu Gln Glu Pro Ser Gln HisArg Thr Gly Ala Ala Val Gln Arg Lys 820 825 830 Pro Trp Pro Ser Gly GlyLeu Trp Arg Gln Asp Gln Gln Pro Gly Pro 835 840 845 Gly Glu Ala Pro HisThr Gln Ala Phe Gly Glu Trp Pro Trp Gly Gln 850 855 860 Glu Leu Gly SerArg Ala Pro Gly Leu Gly Gly Asp Ala Arg Ser Pro 865 870 875 880 Ala ProPro Lys Asn Gly Lys Arg His Asp His Ala Ile Leu Leu Thr 885 890 895 GlyPhe Asp Ile Cys Ser Trp Lys Asn Glu Pro Cys Asp Thr Leu Gly 900 905 910Phe Ala Pro Phe His Ser Ser Ser Tyr Arg Ile Ser Leu Ala Gly Val 915 920925 Glu Pro Ser Leu Val Gln Ala Ala Leu Gly Gln Leu Val Arg Leu Ser 930935 940 Cys Ser Asp Asp Thr Ala Pro Glu Ser Gln Ala Ala Trp Gln Lys Asp945 950 955 960 Gly Gln Pro Ile Ser Ser Asp Arg His Arg Leu Gln Phe AspGly Ser 965 970 975 Leu Ile Ile His Pro Leu Gln Ala Glu Asp Ala Gly ThrTyr Ser Cys 980 985 990 Gly Ser Thr Arg Pro Gly Arg Asp Ser Gln Lys IleGln Leu Arg Ile 995 1000 1005 Ile Gly Leu Cys Pro His Pro Ile His HisSer His Leu Val Ser Pro 1010 1015 1020 Gly Leu Met Thr Gly Gly Asp MetAla Val Leu Ser Glu Ala Glu Leu 1025 1030 1035 1040 Ser Arg Phe Pro GlnPro Arg Asp Pro Ala Gln Asp Phe Gly Gln Ala 1045 1050 1055 Gly Ala AlaGly Pro Leu Gly Ala Ile Pro Ser Ser His Pro Gln Pro 1060 1065 1070 AlaAsn Arg Leu Arg Leu Asp Gln Asn Gln Pro Arg Val Val Asp Ala 1075 10801085 Ser Pro Gly Gln Arg Ile Arg Met Thr Cys Arg Ala Glu Gly Phe Pro1090 1095 1100 Pro Pro Ala Ile Glu Trp Gln Arg Asp Gly Gln Pro Val SerSer Pro 1105 1110 1115 1120 Arg His Gln Leu Gln Pro Asp Gly Ser Leu ValIle Ser Arg Val Ala 1125 1130 1135 Val Glu Asp Gly Gly Phe Tyr Thr CysVal Ala Phe Asn Gly Gln Asp 1140 1145 1150 Arg Asp Gln Arg Trp Val GlnLeu Arg Val Leu Gly Glu Leu Thr Ile 1155 1160 1165 Ser Gly Leu Pro ProThr Val Thr Val Pro Glu Gly Asp Thr Ala Arg 1170 1175 1180 Leu Leu CysVal Val Ala Gly Glu Ser Val Asn Ile Arg Trp Ser Arg 1185 1190 1195 1200Asn Gly Leu Pro Val Gln Ala Asp Gly His Arg Val His Gln Ser Pro 12051210 1215 Asp Gly Thr Leu Leu Ile Tyr Asn Leu Arg Ala Arg Asp Glu GlySer 1220 1225 1230 Tyr Thr Cys Ser Ala Tyr Gln Gly Ser Gln Ala Val SerArg Ser Thr 1235 1240 1245 Glu Val Lys Val Val Ser Pro Ala Pro Thr AlaGln Pro Arg Asp Pro 1250 1255 1260 Gly Arg Asp Cys Val Asp Gln Pro GluLeu Ala Asn Cys Asp Leu Ile 1265 1270 1275 1280 Leu Gln Ala Gln Leu CysGly Asn Glu Tyr Tyr Ser Ser Phe Cys Cys 1285 1290 1295 Ala Ser Cys SerArg Phe Gln Pro His Ala Gln Pro Ile Trp Gln 1300 1305 1310 92 10 PRTArtificial Sequence Consensus amino acid sequence 92 Xaa Xaa Xaa His GluXaa Xaa His Xaa Xaa 1 5 10 93 11 PRT Artificial Sequence Consensus aminoacid sequence 93 His Glu Leu Gly His Asn Leu Gly Met Lys His 1 5 10

What is claimed is:
 1. An isolated 27877, 18080, 14081, 32140, 50352,16658, 14223, 16002, 50566, 65552 or 65577 nucleic acid moleculeselected from the group consisting of: a) a nucleic acid moleculecomprising a nucleotide sequence which is at least 60% identical to thenucleotide sequence of SEQ ID NO: 1, 3, 4, 6, 11, 13, 20, 22, 25, 27,29, 31, 35, 37, 38, 40, 41, 43, 73, 75, 76, 78, 86 or 88, or thenucleotide sequence of the DNA insert of the plasmid deposited with ATCCAccession Number PTA-3217 or PTA-3424; b) a nucleic acid moleculecomprising a fragment of at least 15 nucleotides of the nucleotidesequence of SEQ ID NO: 1, 3, 4, 6, 11, 13, 20, 22, 25, 27, 29, 31, 35,37, 38, 40, 41, 43, 73, 75, 76, 78, 86 or 88, or the nucleotide sequenceof the DNA insert of the plasmid deposited with ATCC Accession NumberPTA-3217 or PTA-3424; c) a nucleic acid molecule which encodes apolypeptide comprising the amino acid sequence of SEQ ID NO: 2, 5, 12,21, 26, 30, 36, 39, 42, 74, 77 or 87, or the amino acid sequence encodedby the cDNA insert of the plasmid deposited with the ATCC AccessionNumber PTA-3217 or PTA-3424; d) a nucleic acid molecule which encodes afragment of a polypeptide comprising the amino acid sequence of SEQ IDNO: 2, 5, 12, 21, 26, 30, 36, 39, 42, 74, 77 or 87, or the amino acidsequence encoded by the cDNA insert of the plasmid deposited with theATCC Accession Number PTA-3217 or PTA-3424, wherein the fragmentcomprises at least 15 contiguous amino acids of SEQ ID NO: 2, 5, 12, 21,26, 30, 36, 39, 42, 74, 77 or 87, or the amino acid sequence encoded bythe cDNA insert of the plasmid deposited with the ATCC Accession NumberPTA-3217 or PTA-3424; e) a nucleic acid molecule which encodes anaturally occurring allelic variant of a polypeptide comprising theamino acid sequence of SEQ ID NO: 2, 5, 12, 21, 26, 30, 36, 39, 42, 74,77 or 87, or the amino acid sequence encoded by the cDNA insert of theplasmid deposited with the ATCC Accession Number PTA-3217 or PTA-3424,wherein the nucleic acid molecule hybridizes to a nucleic acid moleculecomprising SEQ ID NO: 1, 3, 4, 6, 11, 13, 20, 22, 25, 27, 29, 31, 35,37, 38, 40, 41, 43, 73, 75, 76, 78, 86 or 88, or a complement thereof,under stringent conditions; f) a nucleic acid molecule comprising thenucleotide sequence of SEQ ID NO: 1, 3, 4, 6, 11, 13, 20, 22, 25, 27,29, 31, 35, 37, 38, 40, 41, 43, 73, 75, 76, 78, 86 or 88, or thenucleotide sequence of the DNA insert of the plasmid deposited with ATCCAccession Number PTA-3217 or PTA-3424; and g) a nucleic acid moleculewhich encodes a polypeptide comprising the amino acid sequence of SEQ IDNO: 2, 5, 12, 21, 26, 30, 36, 39, 42, 74, 77 or 87, or the amino acidsequence encoded by the cDNA insert of the plasmid deposited with theATCC Accession Number PTA-3217 or PTA-3424.
 2. The isolated nucleic acidmolecule of claim 1, which is the nucleotide sequence SEQ ID NO: 1, 4,11, 20, 25, 29, 35, 38, 41, 73, 76 or
 86. 3. A host cell which containsthe nucleic acid molecule of claim
 1. 4. An isolated 27877, 18080,14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577polypeptide selected from the group consisting of: a) a polypeptidewhich is encoded by a nucleic acid molecule comprising a nucleotidesequence which is at least 60% identical to a nucleic acid comprisingthe nucleotide sequence of SEQ ID NO: 1, 3, 4, 6, 11, 13, 20, 22, 25,27, 29, 31, 35, 37, 38, 40, 41, 43, 73, 75, 76, 78, 86 or 88, or thenucleotide sequence of the DNA insert of the plasmid deposited with ATCCAccession Number PTA-3217 or PTA-3424, or a complement thereof; b) anaturally occurring allelic variant of a polypeptide comprising theamino acid sequence of SEQ ID NO: 2, 5, 12, 21, 26, 30, 36, 39, 42, 74,77 or 87, or the amino acid sequence encoded by the cDNA insert of theplasmid deposited with the ATCC Accession Number PTA-3217 or PTA-3424,wherein the polypeptide is encoded by a nucleic acid molecule whichhybridizes to a nucleic acid molecule comprising SEQ ID NO: 1, 3, 4, 6,11, 13, 20, 22, 25, 27, 29, 31, 35, 37, 38, 40, 41, 43, 73, 75, 76, 78,86 or 88, or a complement thereof under stringent conditions; c) afragment of a polypeptide comprising the amino acid sequence of SEQ IDNO: 2, 5, 12, 21, 26, 30, 36, 39, 42, 74, 77 or 87, or the amino acidsequence encoded by the cDNA insert of the plasmid deposited with theATCC Accession Number PTA-3217 or PTA-3424, wherein the fragmentcomprises at least 15 contiguous amino acids of SEQ ID NO: 2, 5, 12, 21,26, 30, 36, 39, 42, 74, 77 or 87; and d) the amino acid sequence of SEQID NO: 2, 5, 12, 21, 26, 30, 36, 39, 42, 74, 77 or
 87. 5. An antibodywhich selectively binds to a polypeptide of claim
 4. 6. The polypeptideof claim 4, further comprising heterologous amino acid sequences.
 7. Amethod for producing a polypeptide selected from the group consistingof: a) a polypeptide comprising the amino acid sequence of SEQ ID NO: 2,5, 12, 21, 26, 30, 36, 39, 42, 74, 77 or 87, or the amino acid sequenceencoded by the cDNA insert of the plasmid deposited with the ATCCAccession Number PTA-3217 or PTA-3424; b) a polypeptide comprising afragment of the amino acid sequence of SEQ ID NO: 2, 5, 12, 21, 26, 30,36, 39, 42, 74, 77 or 87, or the amino acid sequence encoded by the cDNAinsert of the plasmid deposited with the ATCC Accession Number PTA-3217or PTA-3424, wherein the fragment comprises at least 15 contiguous aminoacids of SEQ ID NO: 2, 5, 12, 21, 26, 30, 36, 39, 42, 74, 77 or 87, orthe amino acid sequence encoded by the cDNA insert of the plasmiddeposited with the ATCC Accession Number PTA-3217 or PTA-3424; c) anaturally occurring allelic variant of a polypeptide comprising theamino acid sequence of SEQ ID NO: 2, 5, 12, 21, 26, 30, 36, 39, 42, 74,77 or 87, or the amino acid sequence encoded by the cDNA insert of theplasmid deposited with the ATCC Accession Number PTA-3217 or PTA-3424,wherein the polypeptide is encoded by a nucleic acid molecule whichhybridizes to a nucleic acid molecule comprising SEQ ID NO: 1, 3, 4, 6,11, 13, 20, 22, 25, 27, 29, 31, 35, 37, 38, 40, 41, 43, 73, 75, 76, 78,86 or 88; and d) the amino acid sequence of SEQ ID NO: 2, 5, 12, 21, 26,30, 36, 39, 42, 74, 77 or 87; comprising culturing the host cell ofclaim 3 under conditions in which the nucleic acid molecule isexpressed.
 8. A method for detecting the presence of a nucleic acidmolecule of claim 1 or a polypeptide encoded by the nucleic acidmolecule in a sample, comprising: a) contacting the sample with acompound which selectively hybridizes to the nucleic acid molecule ofclaim 1 or binds to the polypeptide encoded by the nucleic acidmolecule; and b) determining whether the compound hybridizes to thenucleic acid or binds to the polypeptide in the sample.
 9. A kitcomprising a compound which selectively hybridizes to a nucleic acidmolecule of claim 1 or binds to a polypeptide encoded by the nucleicacid molecule and instructions for use.
 10. A method for identifying acompound which binds to a polypeptide or modulates the activity of thepolypeptide of claim 4 comprising the steps of: a) contacting apolypeptide, or a cell expressing a polypeptide of claim 4 with a testcompound; and b) determining whether the polypeptide binds to the testcompound or determining the effect of the test compound on the activityof the polypeptide.
 11. A method for modulating the activity of apolypeptide of claim 4 comprising contacting the polypeptide or a cellexpressing the polypeptide with a compound which binds to thepolypeptide in a sufficient concentration to modulate the activity ofthe polypeptide.
 12. A method for identifying a compound capable oftreating a disorder characterized by aberrant 27877, 18080, 14081,32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 activity,comprising assaying the ability of the compound to modulate 27877,18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577nucleic acid expression or 27877, 18080, 14081, 32140, 50352, 16658,14223, 16002, 50566, 65552 or 65577 polypeptide activity, therebyidentifying a compound capable of treating a disorder. characterized byaberrant 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566,65552 or 65577 activity.
 13. A method of identifying a nucleic acidmolecule associated with a disorder characterized by aberrant 27877,18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577activity, comprising: a) contacting a sample from a subject with adisorder characterized by aberrant 27877, 18080, 14081, 32140, 50352,16658, 14223, 16002, 50566, 65552 or 65577 activity, comprising nucleicacid molecules with a hybridization probe comprising at least 25contiguous nucleotides of SEQ ID NO: 1, 4, 11, 20, 25, 29, 35, 38, 41,73, 76 or 86 defined in claim 2; and b) detecting the presence of anucleic acid molecule in the sample that hybridizes to the probe,thereby identifying a nucleic acid molecule associated with a disordercharacterized by aberrant 27877, 18080, 14081, 32140, 50352, 16658,14223, 16002, 50566, 65552 or 65577 activity.
 14. A method ofidentifying a polypeptide associated with a disorder characterized byaberrant 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566,65552 or 65577 activity, comprising: a) contacting a sample comprisingpolypeptides with a 27877, 18080, 14081, 32140, 50352, 16658, 14223,16002, 50566, 65552 or 65577 polypeptide defined in claim 4; and b)detecting the presence of a polypeptide in the sample that binds to the27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or65577 binding partner, thereby identifying the polypeptide associatedwith a disorder characterized by aberrant 27877, 18080, 14081, 32140,50352, 16658, 14223, 16002, 50566, 65552 or 65577 activity.
 15. A methodof identifying a subject having a disorder characterized by aberrant27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or65577 activity, comprising: a) contacting a sample obtained from thesubject comprising nucleic acid molecules with a hybridization probecomprising at least 25 contiguous nucleotides of SEQ ID NO: 1, 4, 11,20, 25, 29, 35, 38, 41, 73, 76 or 86 defined in claim 2; and b)detecting the presence of a nucleic acid molecule in the sample thathybridizes to the probe, thereby identifying a subject having a disordercharacterized by aberrant 27877, 18080, 14081, 32140, 50352, 16658,14223, 16002, 50566, 65552 or 65577 activity.
 16. A method for treatinga subject having a disorder characterized by aberrant 27877, 18080,14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577activity, or a subject at risk of developing a disorder characterized byaberrant 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566,65552 or 65577 activity, comprising administering to the subject a27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566, 65552 or65577 modulator of the nucleic acid molecule defined in claim 1 or thepolypeptide encoded by the nucleic acid molecule or contacting a cellwith a 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002, 50566,65552 or 65577 modulator.
 17. The method defined in claim 16 whereinsaid disorder is a cellular proliferative and/or differentiativedisorder, brain disorder, blood vessel disorder, platelet disorder,breast disorder, colon disorder, kidney disorder, lung disorder, ovariandisorder, prostate disorder, hematopoeitic disorder, pancreaticdisorder, skeletal muscle disorder, testicular disorder, skin disorder,hormonal disorder, disorder associated with bone metabolism, immunee.g., inflammatory disorder, cardiovascular disorder, endothelial celldisorder, liver disorder, viral disease, pain, metabolic disorder,anemia, angiogenesic disorder, neoplastic disorder, endocrine disorder,neurological disorder or heart disorder.
 18. The method of claim 16,wherein the 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577 modulator is a) a small molecule; b) peptide; c)phosphopeptide; d) anti-27877, 18080, 14081, 32140, 50352, 16658, 14223,16002, 50566, 65552 or 65577 antibody; e) a 27877, 18080, 14081, 32140,50352, 16658, 14223, 16002, 50566, 65552 or 65577 polypeptide comprisingthe amino acid sequence of SEQ ID NO: 2, 5, 12, 21, 26, 30, 36, 39, 42,74, 77 or 87, or a fragment thereof; f) a 27877, 18080, 14081, 32140,50352, 16658, 14223, 16002, 50566, 65552 or 65577 polypeptide comprisingan amino acid sequence which is at least 90 percent identical to theamino acid sequence of SEQ ID NO: 2, 5, 12, 21, 26, 30, 36, 39, 42, 74,77 or 87, wherein the percent identity is calculated using the ALIGNprogram for comparing amino acid sequences, a PAM120 weight residuetable, a gap length penalty of 12, and a gap penalty of 4; or g) anisolated naturally occurring allelic variant of a polypeptide consistingof the amino acid sequence of SEQ ID NO: 2, 5, 12, 21, 26, 30, 36, 39,42, 74, 77 or 87, wherein the polypeptide is encoded by a nucleic acidmolecule which hybridizes to a complement of a nucleic acid moleculeconsisting of SEQ ID NO: 1, 4, 11, 20, 25, 29, 35, 38, 41, 73, 76 or 86at 6×SSC at 45° C., followed by one or more washes in 0.2X SSC, 0.1% SDSat 65° C.
 19. The method of claim 16, wherein the 27877, 18080, 14081,32140, 50352, 16658, 14223, 16002, 50566, 65552 or 65577 modulator is a)an antisense 27877, 18080, 14081, 32140, 50352, 16658, 14223, 16002,50566, 65552 or 65577 nucleic acid molecule; b) is a ribozyme; c) thenucleotide sequence of SEQ ID NO: 1, 4, 11, 20, 25, 29, 35, 38, 41, 73,76 or 86 or a fragment thereof; d) a nucleic acid molecule encoding apolypeptide comprising an amino acid sequence which is at least 90percent identical to the amino acid sequence of SEQ ID NO: 2, 5, 12, 21,26, 30, 36, 39, 42, 74, 77 or 87, wherein the percent identity iscalculated using the ALIGN program for comparing amino acid sequences, aPAM120 weight residue table, a gap length penalty of 12, and a gappenalty of 4; e) a nucleic acid molecule encoding a naturally occurringallelic variant of a polypeptide comprising the amino acid sequence ofSEQ ID NO: 2, 5, 12, 21, 26, 30, 36, 39, 42, 74, 77 or 87, wherein thenucleic acid molecule which hybridizes to a complement of a nucleic acidmolecule consisting of SEQ ID NO: 1, 4, 11, 20, 25, 29, 35, 38, 41, 73,76 or 86 at 6×SSC at 45° C, followed by one or more washes in 0.2×SSC,0.1% SDS at 65° C.; or f) a gene therapy vector.